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Sample records for dose response relationships

  1. 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

  2. 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

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

    PubMed Central

    Iavicoli, Ivo; Carelli, Giovanni; Marinaccio, Alessandro

    2006-01-01

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

  4. 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)

  5. 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

  6. 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

  7. 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

  8. RELATIONSHIP BETWEEN DELIVERED OZONE DOSE AND FUNCTIONAL RESPONSES IN HUMANS

    EPA Science Inventory

    The relationship between delivered ozone dose and variability of pulmonary function response to ozone was investigated in 20 young, healthy non-smoking male volunteers. he subjects were exposed to 0.4 ppm ozone for one hour during which they walked on a treadmill at a speed and i...

  9. Optimal dose-response relationships in voice therapy.

    PubMed

    Roy, Nelson

    2012-10-01

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

  10. 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.

  11. Confidence bounds for nonlinear dose-response relationships.

    PubMed

    Baayen, C; Hougaard, P

    2015-11-30

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

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

    PubMed

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

    2013-08-01

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

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

    PubMed

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

    2016-07-01

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

  14. 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...

  15. Computer Simulation of Quantal Dose-Response Relationships.

    ERIC Educational Resources Information Center

    McGilliard, Kip L.

    1985-01-01

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

  16. 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

  17. GENERAL CONSIDERATIONS OF DOSE-EFFECT AND DOSE-RESPONSE RELATIONSHIPS

    EPA Science Inventory

    ABSTRACT In 2003, the International Union of Pure and Applied chemistry (IUPAC) issued a glossary of terms that included the defi nition of dose-effect and doseresponse relationships (Nordberg et al., 2004). Dose effect relationship is defined as an association between dose and...

  18. 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...

  19. 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...

  20. Mill effect and dose-response relationships in byssinosis.

    PubMed Central

    Jones, R N; Diem, J E; Glindmeyer, H; Dharmarajan, V; Hammad, Y Y; Carr, J; Weill, H

    1979-01-01

    Four hundred and eighty-six textile workers in three cotton mills and one wool/synthetic mill were studied for symptoms and functional effects of workroom exposure to dust. Byssinosis was found in 5.7% of 386 cotton workers, with an apparent threshold level of 0.5 mg cotton dust/m3 of air. Mean post-shift functional declines were greater in workers exposed to greater than or equal to 0.2 mg/m3. Workers with byssinosis were unequally distributed, however, with respect to job category and mill; and these variables, rather than current dust exposure levels, accounted for the observed distribution of byssinosis prevalence rates. Variation in biological potency of different samples of cotton dust could be responsible for 'mill effect', the residual variation in response rates by mill after controlling for variation due to dust exposure. A number of other potential influencing variables that are likely to be distributed unequally by mill should also be considered. Mill effect should be assessed in large-scale studies of byssinosis, most of which have analysed biological response rates by combining mill and other variables to examine first-order effects of dust dosage. In such analyses, much of the observed variability may be due to factors other than dust dosage. PMID:508642

  1. 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...

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

    PubMed

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

    2009-06-01

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

  3. 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

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

    ERIC Educational Resources Information Center

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

    2008-01-01

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

  5. 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 ...

  6. 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

  7. Characterization of the relationship between dose and blood eosinophil response following subcutaneous administration of mepolizumab

    PubMed Central

    Pouliquen, Isabelle J.; Kornmann, Oliver; Barton, Sharon V.; Price, Jeffrey A.; Ortega, Hector G.

    2015-01-01

    Objective: Mepolizumab is a humanized IgG1 monoclonal antibody that blocks human IL-5 from binding to the IL-5 receptor, which is mainly expressed on eosinophils. Eosinophils are key cells in the inflammatory cascade of various diseases, including asthma. This study investigated the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between exposure of mepolizumab subcutaneous (SC) administration and blood eosinophil reduction compared with intravenous (IV) administration in adult subjects with asthma. Methods: In this multi-center, randomized, open-label, parallel-group, repeat-dose study, 70 adult subjects received one of four possible treatment regimens: mepolizumab 12.5, 125, or 250 mg SC or 75 mg IV. In addition to analyzing the dose and PK/PD relationship, absolute bioavailability, safety, tolerability, and incidence of anti-mepolizumab antibodies were evaluated. Results: Blood eosinophil levels decreased in a dose-dependent manner with the lowest (12.5 mg) dose clearly differentiating from the other doses. A non-linear inhibition Imax model based on blood eosinophil levels at week 12 identified that the SC doses providing 50% and 90% of maximal blood eosinophil inhibition were 11 mg (95% confidence interval (CI): 5.19 – 16.85) and 99 mg (95% CI: 47 – 152), respectively. The route of administration did not affect the exposure-response relationship. The estimated mepolizumab SC absolute bioavailability (arm) was 74% (90% CI: 54 – 102%). The safety profile of mepolizumab was favorable. Conclusions: A dose-dependent reduction in blood eosinophils across all mepolizumab doses investigated was observed. The subcutaneous absolute bioavailability was 74%. The route of administration did not affect the mepolizumab exposure eosinophil response relationship. PMID:26445140

  8. 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

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

    PubMed Central

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

    2010-01-01

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

  10. Dose-Response Relationship for Image-Guided Stereotactic Body Radiotherapy of Pulmonary Tumors: Relevance of 4D Dose Calculation

    SciTech Connect

    Guckenberger, Matthias Wulf, Joern; Mueller, Gerd; Krieger, Thomas; Baier, Kurt; Gabor, Manuela; Richter, Anne; Wilbert, Juergen; Flentje, Michael

    2009-05-01

    Purpose: To evaluate outcome after image-guided stereotactic body radiotherapy (SBRT) for early-stage non-small-cell lung cancer (NSCLC) and pulmonary metastases. Methods and Materials: A total of 124 patients with 159 pulmonary lesions (metastases n = 118; NSCLC, n = 41; Stage IA, n = 13; Stage IB, n = 19; T3N0, n = 9) were treated with SBRT. Patients were treated with hypofractionated schemata (one to eight fractions of 6-26 Gy); biologic effective doses (BED) to the clinical target volume (CTV) were calculated based on four-dimensional (4D) dose calculation. The position of the pulmonary target was verified using volume imaging before all treatments. Results: With mean/median follow-up of 18/14 months, actuarial local control was 83% at 36 months with no difference between NSCLC and metastases. The dose to the CTV based on 4D dose calculation was closely correlated with local control: local control rates were 89% and 62% at 36 months for >100 Gy and <100 Gy BED (p = 0.0001), respectively. Actuarial freedom from regional and systemic progression was 34% at 36 months for primary NSCLC group; crude rate of regional failure was 15%. Three-year overall survival was 37% for primary NSCLC and 16% for metastases; no dose-response relationship for survival was observed. Exacerbation of comorbidities was the most frequent cause of death for primary NSCLC. Conclusions: Doses of >100 Gy BED to the CTV based on 4D dose calculation resulted in excellent local control rates. This cutoff dose is not specific to the treatment technique and protocol of our study and may serve as a general recommendation.

  11. 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

  12. 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

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

    PubMed

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

    2013-08-01

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

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

    PubMed

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

    2014-07-30

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

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

    PubMed Central

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

    2013-01-01

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

  16. Dose-Volume Response Relationship for Brain Metastases Treated with Frameless Single-Fraction Linear Accelerator-Based Stereotactic Radiosurgery

    PubMed Central

    Pan, Jianmin; Yusuf, Mehran B; Dragun, Anthony; Dunlap, Neal; Guan, Timothy; Boling, Warren; Rai, Shesh; Woo, Shiao

    2016-01-01

    Background: Our aim was to identify a dose-volume response relationship for brain metastases treated with frameless stereotactic radiosurgery (SRS). Methods: We reviewed patients who underwent frameless single-fraction linear accelerator SRS for brain metastases between 2007 and 2013 from an institutional database. Proportional hazards modeling was used to identify predictors of outcome. A ratio of maximum lesion dose per mm-diameter (Gy/mm) was constructed to establish a dose-volume relationship. Results: There were 316 metastases evaluated in 121 patients (2 - 33 mm in the largest diameter). The median peripheral dose was 18.0 Gy (range: 10.0 – 24.0 Gy). Local control was 84.8% for all lesions and was affected by location, peripheral dose, maximum dose, and lesion size (p values < 0.050). A dose-volume response relationship was constructed using the maximum dose and lesion size. A unit increase in Gy/mm was associated with decreased local failure (p = 0.005). Local control of 80%, 85%, and 90% corresponded to maximum doses per millimeter of 1.67 Gy/mm, 2.86 Gy/mm, and 4.4 Gy/mm, respectively. Toxicity was uncommon and only 1.0% of lesions developed radionecrosis requiring surgery. Conclusions: For brain metastases less than 3 cm, a dose-volume response relationship exists between maximum radiosurgical dose and lesion size, which is predictive of local control. PMID:27284495

  17. 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

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

    PubMed Central

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

    2016-01-01

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

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

    SciTech Connect

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

    1985-10-01

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

  20. 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...

  1. 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

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

    SciTech Connect

    Rowland, R.E.

    1994-05-01

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

  3. Establishment of in vitro 192Ir γ-ray dose-response relationship for dose assessment by the lymphocyte dicentric assay

    NASA Astrophysics Data System (ADS)

    Kowalska, Maria; Meronka, Katarzyna; Szewczak, Kamil

    2012-03-01

    In vitro dose-response relationships are used to describe the relation between dicentric chromosomes and radiation dose for human peripheral blood lymphocytes. The dicentric yield depends on both the dose and the radiation quality. Thus, for reliable dose estimation in vitro dose responses must be determined for different radiation qualities. This paper reports the work for setting up the relationship for the dicentric production in the lymphocytes exposed in vitro to 192Ir g-rays at Central Laboratory for Radiological Protection (CLOR). In a case of a radiation accident in industrial radiography using 192Ir sealed sources, this will be the basis for the indirect evaluation of the g-ray dose to which an accidental victim was exposed.

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

    PubMed

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

    2016-02-01

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

  6. 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

  7. 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.

  8. 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.

  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. Dose-response relationship of ozone-induced airway hyperresponsiveness in unanesthetized guinea pigs

    SciTech Connect

    Nishikawa, M.; Suzuki, S.; Ikeda, H.; Fukuda, T.; Suzuki, J.; Okubo, T. )

    1990-06-01

    The effect of ozone dose (the product of ozone concentration and exposure time) on airway responsiveness was examined in unanesthetized, spontaneously breathing guinea pigs. Airway responsiveness was assessed by measuring specific airway resistance (sRaw) as a function of increasing concentration of inhaled methacholine (Mch) aerosol (the concentration of Mch required in order to double the baseline sRaw: PC200Mch). The airway responsiveness was measured before and at 5 min, 5 h, and 24 h after exposure. A 30-min exposure to 1 ppm ozone (dose 30 ppm.min) did not change PC200Mch at any time after exposure. Both a 90-min exposure to 1 ppm ozone and a 30-min exposure to 3 ppm ozone, which are identical in terms of ozone dose (90 ppm.min), decreased PC200Mch to a similar degree. A 120-min exposure to 3 ppm ozone (360 ppm.min) produced a much greater decrease of PC200Mch at 5 min and 5 h after exposure, compared with low-dose exposure. There was a significant correlation between ozone dose and the change in airway responsiveness. In all groups, the baseline sRaw was increased by approximately 50% at 5 min after exposure, but there was no correlation between the changes in PC200Mch and the baseline sRaw. This study suggests that ozone-induced airway hyperresponsiveness in guinea pigs is closely related to ozone dose.

  11. Doseresponse relationship between noise exposure and the risk of occupational injury

    PubMed Central

    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. PMID:25599757

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

    PubMed

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

    2016-06-01

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

  13. Site-specific dose-response relationships for cancer induction from the combined Japanese A-bomb and Hodgkin cohorts for doses relevant to radiotherapy

    PubMed Central

    2011-01-01

    Background and Purpose Most information on the dose-response of radiation-induced cancer is derived from data on the A-bomb survivors. Since, for radiation protection purposes, the dose span of main interest is between zero and one Gy, the analysis of the A-bomb survivors is usually focused on this range. However, estimates of cancer risk for doses larger than one Gy are becoming more important for radiotherapy patients. Therefore in this work, emphasis is placed on doses relevant for radiotherapy with respect to radiation induced solid cancer. Materials and methods For various organs and tissues the analysis of cancer induction was extended by an attempted combination of the linear-no-threshold model from the A-bomb survivors in the low dose range and the cancer risk data of patients receiving radiotherapy for Hodgkin's disease in the high dose range. The data were fitted using organ equivalent dose (OED) calculated for a group of different dose-response models including a linear model, a model including fractionation, a bell-shaped model and a plateau-dose-response relationship. Results The quality of the applied fits shows that the linear model fits best colon, cervix and skin. All other organs are best fitted by the model including fractionation indicating that the repopulation/repair ability of tissue is neither 0 nor 100% but somewhere in between. Bone and soft tissue sarcoma were fitted well by all the models. In the low dose range beyond 1 Gy sarcoma risk is negligible. For increasing dose, sarcoma risk increases rapidly and reaches a plateau at around 30 Gy. Conclusions In this work OED for various organs was calculated for a linear, a bell-shaped, a plateau and a mixture between a bell-shaped and plateau dose-response relationship for typical treatment plans of Hodgkin's disease patients. The model parameters (α and R) were obtained by a fit of the dose-response relationships to these OED data and to the A-bomb survivors. For any three

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

    PubMed

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

    2016-05-01

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

  15. 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.

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

    NASA Astrophysics Data System (ADS)

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

    2006-11-01

    Radiotherapy treatment outcome models are a complicated function of treatment, clinical and biological factors. Our objective is to provide clinicians and scientists with an accurate, flexible and user-friendly software tool to explore radiotherapy outcomes data and build statistical tumour control or normal tissue complications models. The software tool, called the dose response explorer system (DREES), is based on Matlab, and uses a named-field structure array data type. DREES/Matlab in combination with another open-source tool (CERR) provides an environment for analysing treatment outcomes. DREES provides many radiotherapy outcome modelling features, including (1) fitting of analytical normal tissue complication probability (NTCP) and tumour control probability (TCP) models, (2) combined modelling of multiple dose-volume variables (e.g., mean dose, max dose, etc) and clinical factors (age, gender, stage, etc) using multi-term regression modelling, (3) manual or automated selection of logistic or actuarial model variables using bootstrap statistical resampling, (4) estimation of uncertainty in model parameters, (5) performance assessment of univariate and multivariate analyses using Spearman's rank correlation and chi-square statistics, boxplots, nomograms, Kaplan-Meier survival plots, and receiver operating characteristics curves, and (6) graphical capabilities to visualize NTCP or TCP prediction versus selected variable models using various plots. DREES provides clinical researchers with a tool customized for radiotherapy outcome modelling. DREES is freely distributed. We expect to continue developing DREES based on user feedback.

  17. Dose-Response Relationships in Gene Expression Profiles in Rainbow Trout, Onorhyncus mykiss Exposed to Ethynylestradiol

    SciTech Connect

    Hook, Sharon E.; Skillman, Ann D.; Small, Jack A.; Schultz, Irv R.

    2006-07-10

    Determining how gene expression profiles change with toxicant dose will improve the utility of arrays in identifying biomarkers and modes of toxic action. We exposed isogenic rainbow trout, Onorhyncus mykiss, to 10, 50 or 100 ng/L ethynylestradiol (a xeno-estrogen) for 7 days. Following exposure, fish were euthanized, livers harvested and RNA extracted. Fluorescently labeled cDNA were generated and hybridized against a commercially available Atlantic Salmon/Trout array (GRASP project, University of Victoria) spotted with 16,000 cDNA's. The slides were scanned to measure abundance of a given transcript in each sample relative to controls. Data were analyzed via Genespring (Silicon Genetics) to identify genes with altered expression, as well as to determine gene clustering patterns that can be used as ''expression signatures''. Array results were confirmed via qRT PCR. Our analysis indicates that gene expression profiles varied somewhat with dose. Established biomarkers of exposure to estrogenic chemicals, such as vitellogenin, vitelline envelope proteins, and the estrogen receptor alpha, were induced at every dose. Other genes were dose specific, suggesting that different doses induce distinct physiological responses. These findings demonstrate that cDNA microarrays could be used to identify both toxicant class and relative dose.

  18. Henry S. Kaplan Distinguished Scientist Award 2003. The crooked shall be made straight; dose-response relationships for carcinogenesis.

    PubMed

    Hall, E J

    2004-05-01

    Estimates of radiation-induced malignancies come principally from the atomic (A)-bomb survivors and show an excess incidence of carcinomas that is linearly related to dose from about 5 cGy to 2.5 Gy. Above and below this dose range there is considerable uncertainty about the shape of the dose-response relationship. Both the International Commission of Radiation Protected (ICRP) and the National Council of Radiation Protection (NCRP) suggest that cancer risks at doses lower than those at which direct epidemiological observations are possible should be obtained by a linear extrapolation from higher doses. The demonstrated bystander effect for irradiation exaggerates the consequences of small doses of radiation and implies that a linear extrapolation from high doses would underestimate low dose risks. It is possible to make estimates of the cancer risk of diagnostic radiological procedures. Helical computed tomography in children is of particular interest since it is rapidly increasing in use and the doses involved are close to the lower limit of significance in the A-bomb survivors. For example, an abdominal computed tomographic scan in a 1-year-old child can be estimated to result in a lifetime cancer risk of about 1:1000. In the context of radiotherapy, some normal tissues receive 70 Gy, while a larger volume receives a lower dose, but still far higher than the range for which data are available from the A-bomb survivors. Data are available for the risk of radiation-induced malignancies for patients who received radiotherapy, e.g. for prostate or cervical cancer. New technologies such as intensity modulated radiation therapy could result in a doubling of radiation-induced second cancers since the technique involves a larger total-body dose due to leakage radiation and the dose distribution obtained involves a larger volume of normal tissue exposed to lower radiation doses. PMID:15223765

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

    PubMed

    Liu, Shu-Zheng

    2003-01-01

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

  20. 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,...

  1. Dose and time relationships in the endocrine response of the irradiated adult rat testis

    SciTech Connect

    Delic, J.I.; Hendry, J.H.; Morris, I.D.; Shalet, S.M.

    1986-01-01

    The dose- and time-dependent responses for the interstitial and tubular compartments in irradiated adult rat testes are described. Leydig cell dysfunction, as indicated by increased serum LH (to a maximum of 385% of control after 5 Gy) and decreased serum T (to a minimum of 30% of control after 10 Gy), was observed at 8 weeks postirradiation. Subsequent recovery of Leydig cell function was then observed, so that after 9 months serum T was normal but LH was still marginally elevated. The dysfunction, with a threshold of about 4 to 5 Gy, was associated with a loss of Leydig cells from the testis. Spermatogenic damage was observed; after doses of 3 Gy and above a marked dose-response was recorded as assessed by counts of tubule cross sections exhibiting spermatogenesis. Reduced serum levels of androgen binding protein indicated Sertoli cell dysfunction at 8 weeks after 3 Gy and above, with values of less than one half of those seen in the controls. Serum FSH also was elevated to between 150% and 200% of control, and after 9 months closely reflected androgen binding protein changes. Unlike the Leydig cell, no recovery with time was observed for this aspect of Sertoli cell function.

  2. 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.

  3. 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

  4. Bermudagrass (Cynodon spp) dose-response relationships with clethodim, glufosinate and glyphosate.

    PubMed

    Webster, Theodore M; Hanna, Wayne W; Mullinix, Benjamin G

    2004-12-01

    Greenhouse studies were conducted to evaluate the sensitivity of three commercial cultivars, eight experimental cultivars and common bermudagrass to clethodim, glufosinate and glyphosate. Each herbicide was applied at eight doses. Data were regressed on herbicide dose using a log-logistic curve (R2 = 0.56-0.95 for clethodim, R2 = 0.60-0.94 for glufosinate, and R2 = 0.70-0.96 for glyphosate). The herbicide rate that elicited a 50% plant response (I50) in the bermudagrass cultivars ranged from 0.04 to 0.19 kg ha(-1) clethodim, 0.19 to 1.33 kg ha(-1) glufosinate and 0.34 to 1.14 kg ha(-1) glyphosate. Relative to other cultivars, common bermudagrass was intermediate in its response to clethodim and among the most tolerant cultivars to glufosinate and glyphosate. TifSport was relatively tolerant to clethodim and glufosinate compared with other cultivars, but relatively sensitive to glyphosate. One cultivar, 94-437, was consistently among the most sensitive cultivars to each of the herbicides. While there were differential herbicide tolerances among the tested bermudagrass cultivars, there did not appear to be any naturally occurring herbicide resistance that could be commercially utilized. However, research indicated that breeding efforts should target herbicide resistance that is at least four times the registered use rate. Also, TifSport and Tifway have been identified as suitable representatives of triploid hybrid bermudagrass cultivars to be used to evaluate the success of turfgrass renovation programs. PMID:15578605

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  7. Ozone dose-response relationships for spring oilseed rape and broccoli

    NASA Astrophysics Data System (ADS)

    De Bock, Maarten; Op de Beeck, Maarten; De Temmerman, Ludwig; Guisez, Yves; Ceulemans, Reinhart; Vandermeiren, Karine

    2011-03-01

    Tropospheric ozone is an important air pollutant with known detrimental effects for several crops. Ozone effects on seed yield, oil percentage, oil yield and 1000 seed weight were examined for spring oilseed rape ( Brassica napus cv. Ability). For broccoli ( Brassica oleracea L. cv. Italica cv. Monaco) the effects on fresh marketable weight and total dry weight were studied. Current ozone levels were compared with an increase of 20 and 40 ppb during 8 h per day, over the entire growing season. Oilseed rape seed yield was negatively correlated with ozone dose indices calculated from emergence until harvest. This resulted in an R2 of 0.24 and 0.26 ( p < 0.001) for the accumulated hourly O 3 exposure over a threshold of 40 ppb (AOT40) and the phytotoxic ozone dose above a threshold of 6 nmol m -2 s -1 (POD 6) respectively. Estimated critical levels, above which 5% yield reduction is expected, were 3.7 ppm h and 4.4 mmol m -2 respectively. Our results also confirm that a threshold value of 6 nmol s -1 m -2 projected leaf area, as recommended for agricultural crops (UNECE, Mills, 2004), can indeed be applied for spring oilseed rape. The reduction of oilseed rape yield showed the highest correlation with the ozone uptake during the vegetative growth stage: when only the first 47 days after emergence were used to calculate POD 6, R2 values increased up to 0.476 or even 0.545 when the first 23 days were excluded. The highest ozone treatments, corresponding to the future ambient level by 2100 (IPCC, Meehl et al., 2007), led to a reduction of approximately 30% in oilseed rape seed yield in comparison to the current ozone concentrations. Oil percentage was also significantly reduced in response to ozone ( p < 0.001). As a consequence oil yield was even more severely affected by elevated ozone exposure compared to seed yield: critical levels for oil yield dropped to 3.2 ppm h and 3.9 mmol m -2. For broccoli the applied ozone doses had no effect on yield.

  8. Toxicogenomic analysis of the particle dose- and size-response relationship of silica particles-induced toxicity in mice

    NASA Astrophysics Data System (ADS)

    Lu, Xiaoyan; Jin, Tingting; Jin, Yachao; Wu, Leihong; Hu, Bin; Tian, Yu; Fan, Xiaohui

    2013-01-01

    This study investigated the relationship between particle size and toxicity of silica particles (SP) with diameters of 30, 70, and 300 nm, which is essential to the safe design and application of SP. Data obtained from histopathological examinations suggested that SP of these sizes can all induce acute inflammation in the liver. In vivo imaging showed that intravenously administrated SP are mainly present in the liver, spleen and intestinal tract. Interestingly, in gene expression analysis, the cellular response pathways activated in the liver are predominantly conserved independently of particle dose when the same size SP are administered or are conserved independently of particle size, surface area and particle number when nano- or submicro-sized SP are administered at their toxic doses. Meanwhile, integrated analysis of transcriptomics, previous metabonomics and conventional toxicological results support the view that SP can result in inflammatory and oxidative stress, generate mitochondrial dysfunction, and eventually cause hepatocyte necrosis by neutrophil-mediated liver injury.

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

    PubMed

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

    2015-01-01

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

  10. 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

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

    PubMed

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

    1977-01-01

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

  12. 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.

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

    PubMed

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

    2003-05-01

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

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

    PubMed Central

    Tseng, Wen-Ping

    1977-01-01

    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. ImagesFIGURE 1.FIGURE 2. PMID:908285

  15. Non-Linear Dose-Response Relationships in Biology, Toxicology and Medicine - An International Conference

    SciTech Connect

    Calabrese, Edward J.; Kostecki, Paul T.

    2002-05-28

    Conference abstract book contains seven sections: Plenary-4 abstracts; Chemical-9 abstracts; Radiation-7 abstracts; Ultra Low Doses and Medicine-6 abstracts; Biomedical-11 abstracts; Risk Assessment-5 abstracts and Poster Sessions-25 abstracts. Each abstract was provided by the author/presenter participating in the conference.

  16. [Exercise-induced asthma in children and oral terbutaline. A dose-response relationship study].

    PubMed

    Hertz, B; Fuglsang, G; Holm, E B

    1994-09-26

    We wanted to assess the protective effects on exercise-induced asthma as well as the clinical efficacy and safety of increasing doses of a new sustained-release formulation of terbutaline sulphate in 17 asthmatic children aged 6-12 years (mean 9 years). Placebo, 2, 4, and 6 mg terbutaline were given b.i.d. for 14 days in a randomized, double-blind, cross-over design. At the end of each two week period, an exercise test was performed and plasma terbutaline was measured. Compared with placebo, no significant effect was seen on asthma symptoms monitored at home, or on exercise-induced asthma. The percentage falls in FEV1 after the exercise test were 36, 35, 27 and 28%, after placebo, 4, 8 and 12 mg terbutaline/day, respectively. A small but statistically significant dose-related increase was seen in morning and evening peak expiratory flow (PEF) recordings. It is concluded that continuous treatment, even with high doses or oral terbutaline, does not offer clinically useful protection against exercise-induced asthma. PMID:7985255

  17. A study of dose-response relationships for asbestos associated disease.

    PubMed Central

    Finkelstein, M M

    1985-01-01

    The risk of an asbestos worker developing small irregular opacities on the chest radiograph is related to cumulative exposure to asbestos dust, latency, and smoking habit. In this study the use of residence-time weighted exposure as a "dose metric" was explored in a cohort of asbestos cement workers. It was found that this parameter, which incorporates both exposure concentration and latency, is useful for modelling the risk of small opacities and might also be useful for modelling the risk of mesothelioma. PMID:3845816

  18. Chronic exposure to odorous chemicals in residential areas and effects on human psychosocial health: dose-response relationships.

    PubMed

    Blanes-Vidal, Victoria; Bælum, Jesper; Nadimi, Esmaeil S; Løfstrøm, Per; Christensen, Lars P

    2014-08-15

    Perceived air pollution, including environmental odor pollution, is known to be an environmental stressor that affects individuals' psychosocial health and well-being. However, very few studies have been able to quantify exposure-response associations based on individual-specific residential exposures to a proxy gas and to examine the mechanisms underlying these associations. In this study, individual-specific exposures in non-urban residential environments during 2005-2010 on a gas released from animal biodegradable wastes (ammonia, NH3) were calculated by the Danish Eulerian long-range transport model and the local-scale transport deposition model. We used binomial and multinomial logistic regression and mediation analyses to examine the associations between average exposures and questionnaire-based data on psychosocial responses, after controlling for person-specific covariates. About 45% of the respondents were annoyed by residential odor pollution. Exposures were associated with annoyance (adjusted odds ratio [ORadj]=3.54, 95% confidence interval [CI]=2.33-5.39), health risk perception (ORadj=4.94; 95% CI=1.95-12.5) and behavioral interference (ORadj=3.28; 95% CI=1.77-6.11), for each unit increase in loge(NH3 exposure). Annoyance was a strong mediator in exposure-behavior interference and exposure-health risk perception relationships (81% and 44% mediation, respectively). Health risk perception did not play a mediating role in exposure-annoyance or exposure-behavioral interference relationships. This is the first study to provide a quantitative estimation of the dose-response associations between ambient NH3 exposures and psychosocial effects caused by odor pollution in non-urban residential outdoor environments. It further shows that these effects are both direct and mediated by other psychosocial responses. The results support the use of NH3 as a proxy gas of air pollution from animal biodegradable wastes in epidemiologic studies. PMID:24880544

  19. Analysis of dose/time/response relationships for chronic toxic effects: the case of acrylamide

    SciTech Connect

    Hattis, D.; Shapiro, K.

    1988-07-01

    To conduct a risk assessment of hazards associated with the handling of acrylamide, a simple dynamic-analysis model was applied to the results of some classic studies of acrylamide neurotoxicity. The model incorporated the following assumptions: that a particular adverse effect occurs whenever a specific amount of damage is accumulated in the relevant portions of the nervous system, that damage is produced at a rate linear with the dose administered, and that repair of the accumulated damage occurs at a rate directly dependent on the amount of accumulated damage to be repaired. Preliminary estimates were proposed of the risk posed to various proportions of the population by exposure to various air concentrations of acrylamide. For the most part the model focused on the reversible neurotoxic damage and its associated rates of repair. However, there was also evidence that some of the damage from acrylamide is not reversible. At ventilation rate of 10 cubic meters per 8 hour day, a 5-year exposure to acrylamide at 1.5 mg/cu m or a 40-year exposure to 0.18 mg/cu m would show an association to long term visual changes in average individuals.

  20. Latency, duration and dose response relationships of amino acid effects on human muscle protein synthesis.

    PubMed

    Rennie, Michael J; Bohé, Julien; Wolfe, Robert R

    2002-10-01

    The components of the stimulatory effect of food on net deposition of protein are beginning to be identified and separated. One of the most important of these appears to be the effect of amino acids per se in stimulating muscle anabolism. Amino acids appear to have a linear stimulatory effect within the range of normal diurnal plasma concentrations from postabsorptive to postprandial. Within this range, muscle protein synthesis (measured by incorporation of stable isotope tracers of amino acids into biopsied muscle protein) appears to be stimulated approximately twofold; however, little further increase occurs when very high concentrations of amino acids (>2.5 times the normal postabsorptive plasma concentration) are made available. Amino acids provided in surfeit of the ability of the system to synthesize protein are disposed of by oxidation, ureagenesis and gluconeogenesis. The stimulatory effect of amino acids appears to be time dependent; a square wave increase in the availability of amino acids causes muscle protein synthesis to be stimulated and to fall back to basal values, despite continued amino acid availability. The relationship between muscle protein synthesis and insulin availability suggests that most of the stimulatory effects occur at low insulin concentrations, with large increases having no effect. These findings may have implications for our understanding of the body's requirements for protein. The maximal capacity for storage of amino acids as muscle protein probably sets an upper value on the extent to which amino acids can be stored after a single meal. PMID:12368422

  1. Dose-response relationships for resetting of human circadian clock by light

    NASA Technical Reports Server (NTRS)

    Boivin, D. B.; Duffy, J. F.; Kronauer, R. E.; Czeisler, C. A.

    1996-01-01

    Since the first report in unicells, studies across diverse species have demonstrated that light is a powerful synchronizer which resets, in an intensity-dependent manner, endogenous circadian pacemakers. Although it is recognized that bright light (approximately 7,000 to 13,000 lux) is an effective circadian synchronizer in humans, it is widely believed that the human circadian pacemaker is insensitive to ordinary indoor illumination (approximately 50-300 lux). It has been proposed that the relationship between the resetting effect of light and its intensity follows a compressive nonlinear function, such that exposure to lower illuminances still exerts a robust effect. We therefore undertook a series of experiments which support this hypothesis and report here that light of even relatively low intensity (approximately 180 lux) significantly phase-shifts the human circadian pacemaker. Our results clearly demonstrate that humans are much more sensitive to light than initially suspected and support the conclusion that they are not qualitatively different from other mammals in their mechanism of circadian entrainment.

  2. Dose-response relationship of the cardiovascular adaptation to endurance training in healthy adults: how much training for what benefit?

    PubMed

    Iwasaki, Ken-Ichi; Zhang, Rong; Zuckerman, Julie H; Levine, Benjamin D

    2003-10-01

    Occupational or recreational exercise reduces mortality from cardiovascular disease. The potential mechanisms for this reduction may include changes in blood pressure (BP) and autonomic control of the circulation. Therefore, we conducted the present long-term longitudinal study to quantify the dose-response relationship between the volume and intensity of exercise training, and regulation of heart rate (HR) and BP. We measured steady-state hemodynamics and analyzed dynamic cardiovascular regulation by spectral and transfer function analysis of cardiovascular variability in 11 initially sedentary subjects during 1 yr of progressive endurance training sufficient to allow them to complete a marathon. From this, we found that 1) moderate exercise training for 3 mo decreased BP, HR, and total peripheral resistance, and increased cardiovascular variability and arterial baroreflex sensitivity; 2) more prolonged and intense training did not augment these changes further; and 3) most of these changes returned to control values at 12 mo despite markedly increased training duration and intensity equivalent to that routinely observed in competitive athletes. In conclusion, increases in R-wave-R-wave interval and cardiovascular variability indexes are consistent with an augmentation of vagal modulation of HR after exercise training. It appears that moderate doses of training for 3 mo are sufficient to achieve this response as well as a modest hypotensive effect from decreasing vascular resistance. However, more prolonged and intense training does not necessarily lead to greater enhancement of circulatory control and, therefore, may not provide an added protective benefit via autonomic mechanisms against death by cardiovascular disease. PMID:12832429

  3. Dose-response relationships of polycyclic aromatic hydrocarbons exposure and oxidative damage to DNA and lipid in coke oven workers.

    PubMed

    Kuang, Dan; Zhang, Wangzhen; Deng, Qifei; Zhang, Xiao; Huang, Kun; Guan, Lei; Hu, Die; Wu, Tangchun; Guo, Huan

    2013-07-01

    Polycyclic aromatic hydrocarbons (PAHs) are known to induce reactive oxygen species and oxidative stress, but the dose-response relationships between exposure to PAHs and oxidative stress levels have not been established. In this study, we recruited 1333 male coke oven workers, monitored the levels of environmental PAHs, and measured internal PAH exposure biomarkers including 12 urinary PAH metabolites and plasma benzo[a]pyrene-r-7,t-8,t-9,c-10-tetrahydotetrol-albumin (BPDE-Alb) adducts, as well as the two oxidative biomarkers urinary 8-hydroxydeoxyguanosine (8-OHdG) and 8-iso-prostaglandin-F2α (8-iso-PGF2α). We found that the total concentration of urinary PAH metabolites and plasma BPDE-Alb adducts were both significantly associated with increased 8-OHdG and 8-iso-PGF2α in both smokers and nonsmokers (all p < 0.05). This exposure-response effect was also observed for most PAH metabolites (all p(trend) < 0.01), except for 4-hydroxyphenanthrene and 8-OHdG (p(trend) = 0.108). Furthermore, it was shown that only urinary 1-hydroxypyrene has a significant positive association with both 8-OHdG and 8-iso-PGF2α after a Bonferroni correction (p < 0.005). Our results indicated that urinary ΣOH-PAHs and plasma BPDE-Alb adducts can result in significant dose-related increases in oxidative damage to DNA and lipids. Furthermore, when a multianalyte method is unavailable, our findings demonstrate that urinary 1-hydroxypyrene is a useful biomarker for evaluating total PAHs exposure and assessing oxidative damage in coke oven workers. PMID:23745771

  4. Home dampness, childhood asthma, hay fever, and airway symptoms in Shanghai, China: associations, dose-response relationships, and lifestyle's influences.

    PubMed

    Hu, Y; Liu, W; Huang, C; Zou, Z J; Zhao, Z H; Shen, L; Sundell, J

    2014-10-01

    Numerous studies of associations between dampness and respiratory diseases have been conducted, but their implications remain inconclusive. In this study of 13,335 parent-reported questionnaires (response rate: 85.3%), we analyzed associations between home dampness and asthma and related symptoms in 4- to 6-year-old children in a cross-sectional study of Shanghai. Indicators of home dampness were strongly and significantly associated with dry cough, wheeze, and rhinitis symptoms. In the current residence, children with visible mold spots (VMS) exposure had 32% higher risk of asthma (adjusted OR, 95% CI: 1.32, 1.07-1.64); damp clothing and/or bedding (frequently) was strongly associated with dry cough (1.78, 1.37-2.30); condensation on windows was strongly associated with hay fever (1.60, 1.27-2.01). In the early-life residence, VMS or damp stains (frequently) were strongly associated with dry cough (2.20, 1.55-3.11) and rhinitis ever (1.57, 1.11-2.21). Associations between dampness and diseases among children with or without family history of atopy were similar. The total number of dampness indicators had strong dose-response relationships with investigated health outcomes. Actions, including opening windows of the child's room at night and cleaning the child's room frequently, could potentially mitigate 25% of home VMS, thereby preventing more than 1.5% of attributable risk of the studied symptoms. PMID:24571077

  5. 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.

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

    PubMed

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

    2013-01-01

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

  7. Optimization of radotinib doses for the treatment of Asian patients with chronic myelogenous leukemia based on dose-response relationship analyses.

    PubMed

    Noh, Hayeon; Park, Min Soo; Kim, Sung-Hyun; Oh, Suk Joong; Zang, Dae Young; Park, Hye Lin; Cho, Dae Jin; Kim, Dong-Wook; Lee, Jangik I

    2016-08-01

    A fixed dose regimen for tyrosine kinase inhibitors (TKIs) is postulated to be responsible for variable safety outcomes in the treatment of chronic myelogenous leukemia (CML). The objective of this study was to explore an optimal dosing regimen for a TKI, radotinib, to improve its safety profile. Clinical data were obtained from a Phase 2 study of fixed-dose radotinib in 77 Asian patients with CML. The magnitude of radotinib dose adjusted for patient's body weight (Dose/BW) and the probability of dose-limiting toxicity (DLT) demonstrated a positive association (Logit[P] = 0.86*[Dose/BW]-4.45, p = 0.001). There was a significant difference in the Kaplan-Meier curves for time to first DLT between the patient subgroups of Dose/BW <6 and ≥6 mg/kg (259 versus 83 days). Consequently, a two-tier weight-based dosing regimen may improve the safety of radotinib: 300 mg or 400 mg twice daily for patients weighing ≤65 or >65 kg, respectively. PMID:26666371

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

    PubMed

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

    2009-01-01

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

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

    PubMed Central

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

    2009-01-01

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  11. A dose-response relationship between maternal smoking during late pregnancy and adult intelligence in male offspring.

    PubMed

    Mortensen, Erik Lykke; Michaelsen, Kim Fleischer; Sanders, Stephanie A; Reinisch, June Machover

    2005-01-01

    An association between maternal smoking during pregnancy and cognitive and behavioural development has been observed in several studies, but potential effects of maternal smoking on offspring adult intelligence have not been investigated. The objective of the present study was to investigate a potential association between maternal smoking during pregnancy and offspring intelligence in young adulthood. Adult intelligence was assessed at the mean age of 18.7 years by a military draft board intelligence test (Borge Priens Prove) for 3044 singleton males from the Copenhagen Perinatal Cohort with information regarding maternal smoking during the third trimester coded into five categories (about 50% of the mothers were smokers). The following potential confounders were included as covariates in multivariable analyses: parental social status and education, single mother status, mother's height and age, number of pregnancies, and gestational age. In separate analyses, birthweight and length were also included as covariates. Maternal cigarette smoking during the third trimester, adjusted for the seven covariates, showed a negative association with offspring adult intelligence (P=0.0001). The mean difference between the no-smoking and the heaviest smoking category amounted to 0.41 standard deviation, corresponding to an IQ difference of 6.2 points [95% confidence interval 0.14, 0.68]. The association remained significant when further adjusted for birthweight and length (P=0.007). Both unadjusted and adjusted means suggested a dose-response relationship between maternal smoking during pregnancy and offspring adult intelligence. When subjects with missing data were excluded, essentially the same results were obtained in the reduced sample (n=1829). These results suggest that smoking during pregnancy may have long-term negative consequences on offspring adult intelligence. PMID:15670102

  12. Image-Guided Robotic Stereotactic Body Radiation Therapy for Liver Metastases: Is There a Dose Response Relationship?

    SciTech Connect

    Vautravers-Dewas, Claire; Dewas, Sylvain; Bonodeau, Francois; Adenis, Antoine; Lacornerie, Thomas; Penel, Nicolas; Lartigau, Eric; Mirabel, Xavier

    2011-11-01

    Purpose: To evaluate the outcome, tolerance, and toxicity of stereotactic body radiotherapy, using image-guided robotic radiation delivery, for the treatment of patients with unresectable liver metastases. Methods and Material: Patients were treated with real-time respiratory tracking between July 2007 and April 2009. Their records were retrospectively reviewed. Metastases from colorectal carcinoma and other primaries were not necessarily confined to liver. Toxicity was evaluated using National Cancer Institute Common Criteria for Adverse Events version 3.0. Results: Forty-two patients with 62 metastases were treated with two dose levels of 40 Gy in four Dose per Fraction (23) and 45 Gy in three Dose per Fraction (13). Median follow-up was 14.3 months (range, 3-23 months). Actuarial local control for 1 and 2 years was 90% and 86%, respectively. At last follow-up, 41 (66%) complete responses and eight (13%) partial responses were observed. Five lesions were stable. Nine lesions (13%) were locally progressed. Overall survival was 94% at 1 year and 48% at 2 years. The most common toxicity was Grade 1 or 2 nausea. One patient experienced Grade 3 epidermitis. The dose level did not significantly contribute to the outcome, toxicity, or survival. Conclusion: Image-guided robotic stereotactic body radiation therapy is feasible, safe, and effective, with encouraging local control. It provides a strong alternative for patients who cannot undergo surgery.

  13. 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

  14. Repetitive TASER X26 discharge resulted in adverse physiologic events with a dose-response relationship related to the duration of discharge in anesthetized swine model.

    PubMed

    Park, Eun-Jung; Choi, Sang-Cheon; Ahn, Jung-Hwan; Min, Young-Gi

    2013-01-01

    The objectives of our study were to investigate the dose-response relationship of the TASER X26 discharge duration in an anesthetized swine model. Fourteen swines were anesthetized and then exposed to TASER X26 discharge for 5 sec (n = 5) or for 10 sec (n = 6). The sham control group (n = 3) was anesthetized and studied using the same protocol except TASER X26 discharges during the experiments. Hemodynamic parameters were obtained. Blood pressure and total peripheral resistance decreased significantly after TASER discharge and returned to baseline value at 15 min after 5 sec of TASER discharge but did not return to baseline values during the 30-min observation period after 10 sec of TASER discharge. Repetitive TASER X26 discharge resulted in adverse physiologic events with a dose-response relationship related to the duration of TASER X26 discharge in an anesthetized swine model. PMID:23066880

  15. Characterizing dose response relationships: Chronic gamma radiation in Lemna minor induces oxidative stress and altered polyploidy level.

    PubMed

    Van Hoeck, Arne; Horemans, Nele; Van Hees, May; Nauts, Robin; Knapen, Dries; Vandenhove, Hildegarde; Blust, Ronny

    2015-12-01

    The biological effects and interactions of different radiation types in plants are still far from understood. Among different radiation types, external gamma radiation treatments have been mostly studied to assess the biological impact of radiation toxicity in organisms. Upon exposure of plants to gamma radiation, ionisation events can cause, either directly or indirectly, severe biological damage to DNA and other biomolecules. However, the biological responses and oxidative stress related mechanisms under chronic radiation conditions are poorly understood in plant systems. In the following study, it was questioned if the Lemna minor growth inhibition test is a suitable approach to also assess the radiotoxicity of this freshwater plant. Therefore, L. minor plants were continuously exposed for seven days to 12 different dose rate levels covering almost six orders of magnitude starting from 80 μGy h(-1) up to 1.5 Gy h(-1). Subsequently, growth, antioxidative defence system and genomic responses of L. minor plants were evaluated. Although L. minor plants could survive the exposure treatment at environmental relevant exposure conditions, higher dose rate levels induced dose dependent growth inhibitions starting from approximately 27 mGy h(-1). A ten-percentage growth inhibition of frond area Effective Dose Rate (EDR10) was estimated at 95 ± 7 mGy h(-1), followed by 153 ± 13 mGy h(-1) and 169 ± 12 mGy h(-1) on fresh weight and frond number, respectively. Up to a dose rate of approximately 5 mGy h(-1), antioxidative enzymes and metabolites remained unaffected in plants. A significant change in catalase enzyme activity was found at 27 mGy h(-1) which was accompanied with significant increases of other antioxidative enzyme activities and shifts in ascorbate and glutathione content at higher dose rate levels, indicating an increase in oxidative stress in plants. Recent plant research hypothesized that environmental genotoxic stress conditions

  16. Time-course and dose-response relationships of imperatorin in the mouse maximal electroshock seizure threshold model.

    PubMed

    Luszczki, Jarogniew J; Glowniak, Kazimierz; Czuczwar, Stanislaw J

    2007-09-01

    This study was designed to evaluate the anticonvulsant effects of imperatorin (a furanocoumarin isolated from fruits of Angelica archangelica) in the mouse maximal electroshock seizure threshold model. The threshold for electroconvulsions in mice was determined at several times: 15, 30, 60 and 120 min after i.p. administration of imperatorin at increasing doses of 10, 20, 30, 40, 50 and 100 mg/kg. The evaluation of time-course relationship for imperatorin in the maximal electroshock seizure threshold test revealed that the agent produced its maximum antielectroshock action at 30 min after its i.p. administration. In this case, imperatorin at doses of 50 and 100 mg/kg significantly raised the threshold for electroconvulsions in mice by 38 and 68% (P<0.05 and P<0.001), respectively. The antiseizure effects produced by imperatorin at 15, 60 and 120 min after its systemic (i.p.) administration were less expressed than those observed for imperatorin injected 30 min before the maximal electroshock seizure threshold test. Based on this study, one can conclude that imperatorin produces the anticonvulsant effect in the maximal electroshock seizure threshold test in a dose-dependent manner. PMID:17602770

  17. Chemical stress and metabolic rate in aquatic invertebrates: Threshold, dose-response relationships, and mode of toxic action

    SciTech Connect

    Penttinen, O.P.; Kukkonen, J.

    1998-01-01

    Four automatic compounds were evaluated in laboratory studies to investigate their accumulation and toxicant-induced changes in the rate of heat dissipation in the freshwater invertebrates Chironomus riparius and Lumbriculus variegatus. The sublethal energetic response detected by direct calorimetry was related to tissue chemical concentration by the threshold model and an attempt was made to apply the critical body residue (CBR) concept. Below the compound-specific tissue threshold concentration or CBR, no correlations were found between the dose and the metabolic rate, and the slopes of the regression were close to zero. Above the threshold, depending on the chemical, metabolic rate either increased or decreased. An increase in heat output produced by 2,4-dinitrophenol (2,4-DNP), pentachlorophenol (PCP), and 2,4,5-trichlorophenol (2,4,5-TCP) was closely correlated with the dose. The order of toxicity for these phenols was 2,4-DNP = PCP > 2,4,5-TCP, which reflects the interaction of compounds` lipophilicities and acidities and their combined influence on bioaccumulation and effects on the energy-transducing membrane by uncoupling oxidative phosphorylation. A decrease in the heat output caused by 1,2,4-trichlorobenzene (1,2,4-TCB) was more variable relative to dose. Also, 1,2,4-TCB required a much higher molar tissue threshold concentration ({approximately}2.0 {micro}mol/g wet weight) than required by phenols to generate the response. Both the metabolic response and the chemical threshold value were those expected to result from narcosis. Results suggest that calorimetric measures can identify not only the integrated physiologic response but also have some resolution of the mechanism of toxic effects.

  18. Modulation of cytochrome P450 2A5 activity by lipopolysaccharide: low-dose effects and non-monotonic dose-response relationship.

    PubMed

    De-Oliveira, Ana C A X; Poça, Kátia S; Totino, Paulo R R; Paumgartten, Francisco J R

    2015-01-01

    Mouse cytochrome P450 (CYP) 2A5 is induced by inflammatory conditions and infectious diseases that down-regulate the expression and activity of most other CYP isoforms. Enhanced oxidative stress and nuclear factor (erythroid 2-related factor) 2 (Nrf2) transcription factor activation have been hypothesised to mediate up-regulation of CYP2A5 expression in the murine liver. The unique and complex regulation of CYP2A5, however, is far from being thoroughly elucidated. Sepsis and high doses of bacterial lipopolysaccharide (LPS) elicit oxidative stress in the liver, but depression, not induction, of CYP2A5 has been observed in studies of mice treated with LPS. The foregoing facts prompted us to evaluate the response of CYP2A5 liver activity in female DBA-2 mice over a broad range of LPS doses (0, 0.025, 0.05, 0.1, 0.2, 0.5, 1, 2, 5, 10, and 20 mg/kg). Cytokine levels (interleukin [IL]-2, IL-4, IL-6, IL-10, IL-17A, interferon gamma, tumour necrosis factor alpha) and nitric oxide (NO) were measured in the blood serum. Activities of CYP1A (EROD) and CYP2B (BROD) in the liver were also determined for comparative purposes. LPS depressed CYP2A5 at low doses (0.025-2.0 mg/kg) but not at doses (>2 mg/kg) that increased pro-inflammatory cytokines and NO serum levels, and depressed CYP1A and CYP2B activities. Blockade of pro-inflammatory cytokines and the overproduction of NO induced by co-treatment with pentoxifylline and LPS and iNOS inhibition with aminoguanidine both extended down-regulation of CYP2A5 to the high dose range while not affecting LPS-induced depression of CYP1A and CYP2B. Overall, the results suggested that NO plays a role in the reversal of the low-dose LPS-induced depression of CYP2A5 observed when mice were challenged with higher doses of LPS. PMID:25635819

  19. Dose-Response Relationship of Physical Activity to Premature and Total All-Cause and Cardiovascular Disease Mortality in Walkers

    PubMed Central

    Williams, Paul T.

    2013-01-01

    Purpose To assess the dose-response relationships between cause-specific mortality and exercise energy expenditure in a prospective epidemiological cohort of walkers. Methods The sample consisted of the 8,436 male and 33,586 female participants of the National Walkers' Health Study. Walking energy expenditure was calculated in metabolic equivalents (METs, 1 MET = 3.5 ml O2/kg/min), which were used to divide the cohort into four exercise categories: category 1 (≤1.07 MET-hours/d), category 2 (1.07 to 1.8 MET-hours/d), category 3 (1.8 to 3.6 MET-hours/d), and category 4 (≥3.6 MET-hours/d). Competing risk regression analyses were use to calculate the risk of mortality for categories 2, 3 and 4 relative to category 1. Results 22.9% of the subjects were in category 1, 16.1% in category 2, 33.3% in category 3, and 27.7% in category 4. There were 2,448 deaths during the 9.6 average years of follow-up. Total mortality was 11.2% lower in category 2 (P = 0.04), 32.4% lower in category 3 (P<10−12) and 32.9% lower in category 4 (P = 10−11) than in category 1. For underlying causes of death, the respective risk reductions for categories 2, 3 and 4 were 23.6% (P = 0.008), 35.2% (P<10−5), and 34.9% (P = 0.0001) for cardiovascular disease mortality; 27.8% (P = 0.18), 20.6% (P = 0.07), and 31.4% (P = 0.009) for ischemic heart disease mortality; and 39.4% (P = 0.18), 63.8% (P = 0.005), and 90.6% (P = 0.002) for diabetes mortality when compared to category 1. For all related mortality (i.e., underlying and contributing causes of death combined), the respective risk reductions for categories 2, 3 and 4 were 18.7% (P = 0.22), 42.5% (P = 0.001), and 57.5% (P = 0.0001) for heart failure; 9.4% (P = 0.56), 44.3% (P = 0.0004), and 33.5% (P = 0.02) for hypertensive diseases; 11.5% (P = 0.38), 41.0% (P<10−4), and 35.5% (P = 0.001) for dysrhythmias: and 23.2% (P = 0.13), 45.8% (P = 0.0002), and 41

  20. Dose-response relationship between serum 2,3,7,8-tetrachlorodibenzo-p-dioxin and diabetes mellitus: a meta-analysis.

    PubMed

    Goodman, Michael; Narayan, K M Venkat; Flanders, Dana; Chang, Ellen T; Adami, Hans-Olov; Boffetta, Paolo; Mandel, Jack S

    2015-03-15

    We systematically evaluated studies published through May 2014 in which investigators assessed the dose-response relationship between serum levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the occurrence of diabetes mellitus (DM), and we investigated the extent and sources of interstudy heterogeneity. The dose-response relationship between serum TCDD and DM across studies was examined using 2 dependent variables: an exposure level-specific proportion of persons with DM and a corresponding natural log-transformed ratio measure of the association between TCDD and DM. Regression slopes for each dependent variable were obtained for each study and included in a random-effects meta-analysis. Sensitivity analyses were used to assess the influence of inclusion and exclusion decisions, and sources of heterogeneity were explored using meta-regression models and a series of subanalyses. None of the summary estimates in the main models or in the sensitivity analyses indicated a statistically significant association. We found a pronounced dichotomy: a positive dose-response in cross-sectional studies of populations with low-level TCDD exposures (serum concentrations <10 pg/g lipid) and heterogeneous, but on balance null, results for prospective studies of persons with high prediagnosis TCDD body burdens. Considering the discrepancy of results for low current versus high past TCDD levels, the available data do not indicate that increasing TCDD exposure is associated with an increased risk of DM. PMID:25731889

  1. Dose-Response Relationship Between Serum 2,3,7,8-Tetrachlorodibenzo-p-Dioxin and Diabetes Mellitus: A Meta-Analysis

    PubMed Central

    Goodman, Michael; Narayan, K. M. Venkat; Flanders, Dana; Chang, Ellen T.; Adami, Hans-Olov; Boffetta, Paolo; Mandel, Jack S.

    2015-01-01

    We systematically evaluated studies published through May 2014 in which investigators assessed the dose-response relationship between serum levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the occurrence of diabetes mellitus (DM), and we investigated the extent and sources of interstudy heterogeneity. The dose-response relationship between serum TCDD and DM across studies was examined using 2 dependent variables: an exposure level–specific proportion of persons with DM and a corresponding natural log-transformed ratio measure of the association between TCDD and DM. Regression slopes for each dependent variable were obtained for each study and included in a random-effects meta-analysis. Sensitivity analyses were used to assess the influence of inclusion and exclusion decisions, and sources of heterogeneity were explored using meta-regression models and a series of subanalyses. None of the summary estimates in the main models or in the sensitivity analyses indicated a statistically significant association. We found a pronounced dichotomy: a positive dose-response in cross-sectional studies of populations with low-level TCDD exposures (serum concentrations <10 pg/g lipid) and heterogeneous, but on balance null, results for prospective studies of persons with high prediagnosis TCDD body burdens. Considering the discrepancy of results for low current versus high past TCDD levels, the available data do not indicate that increasing TCDD exposure is associated with an increased risk of DM. PMID:25731889

  2. Dose-response relationship between arsenic exposure and the serum enzymes for liver function tests in the individuals exposed to arsenic: a cross sectional study in Bangladesh

    PubMed Central

    2011-01-01

    Background Chronic arsenic exposure has been shown to cause liver damage. However, serum hepatic enzyme activity as recognized on liver function tests (LFTs) showing a dose-response relationship with arsenic exposure has not yet been clearly documented. The aim of our study was to investigate the dose-response relationship between arsenic exposure and major serum enzyme marker activity associated with LFTs in the population living in arsenic-endemic areas in Bangladesh. Methods A total of 200 residents living in arsenic-endemic areas in Bangladesh were selected as study subjects. Arsenic concentrations in the drinking water, hair and nails were measured by Inductively Coupled Plasma Mass Spectroscopy (ICP-MS). The study subjects were stratified into quartile groups as follows, based on concentrations of arsenic in the drinking water, as well as in subjects' hair and nails: lowest, low, medium and high. The serum hepatic enzyme activities of alkaline phosphatase (ALP), aspartate transaminase (AST) and alanine transaminase (ALT) were then assayed. Results Arsenic concentrations in the subjects' hair and nails were positively correlated with arsenic levels in the drinking water. As regards the exposure-response relationship with arsenic in the drinking water, the respective activities of ALP, AST and ALT were found to be significantly increased in the high-exposure groups compared to the lowest-exposure groups before and after adjustments were made for different covariates. With internal exposure markers (arsenic in hair and nails), the ALP, AST and ALT activity profiles assumed a similar shape of dose-response relationship, with very few differences seen in the higher groups compared to the lowest group, most likely due to the temporalities of exposure metrics. Conclusions The present study demonstrated that arsenic concentrations in the drinking water were strongly correlated with arsenic concentrations in the subjects' hair and nails. Further, this study revealed a

  3. Dose-response relationship in music therapy for people with serious mental disorders: systematic review and meta-analysis.

    PubMed

    Gold, Christian; Solli, Hans Petter; Krüger, Viggo; Lie, Stein Atle

    2009-04-01

    Serious mental disorders have considerable individual and societal impact, and traditional treatments may show limited effects. Music therapy may be beneficial in psychosis and depression, including treatment-resistant cases. The aim of this review was to examine the benefits of music therapy for people with serious mental disorders. All existing prospective studies were combined using mixed-effects meta-analysis models, allowing to examine the influence of study design (RCT vs. CCT vs. pre-post study), type of disorder (psychotic vs. non-psychotic), and number of sessions. Results showed that music therapy, when added to standard care, has strong and significant effects on global state, general symptoms, negative symptoms, depression, anxiety, functioning, and musical engagement. Significant dose-effect relationships were identified for general, negative, and depressive symptoms, as well as functioning, with explained variance ranging from 73% to 78%. Small effect sizes for these outcomes are achieved after 3 to 10, large effects after 16 to 51 sessions. The findings suggest that music therapy is an effective treatment which helps people with psychotic and non-psychotic severe mental disorders to improve global state, symptoms, and functioning. Slight improvements can be seen with a few therapy sessions, but longer courses or more frequent sessions are needed to achieve more substantial benefits. PMID:19269725

  4. Probabilistic hazard assessment for skin sensitization potency by dose-response modeling using feature elimination instead of quantitative structure-activity relationships.

    PubMed

    Luechtefeld, Thomas; Maertens, Alexandra; McKim, James M; Hartung, Thomas; Kleensang, Andre; Sá-Rocha, Vanessa

    2015-11-01

    Supervised learning methods promise to improve integrated testing strategies (ITS), but must be adjusted to handle high dimensionality and dose-response data. ITS approaches are currently fueled by the increasing mechanistic understanding of adverse outcome pathways (AOP) and the development of tests reflecting these mechanisms. Simple approaches to combine skin sensitization data sets, such as weight of evidence, fail due to problems in information redundancy and high dimensionality. The problem is further amplified when potency information (dose/response) of hazards would be estimated. Skin sensitization currently serves as the foster child for AOP and ITS development, as legislative pressures combined with a very good mechanistic understanding of contact dermatitis have led to test development and relatively large high-quality data sets. We curated such a data set and combined a recursive variable selection algorithm to evaluate the information available through in silico, in chemico and in vitro assays. Chemical similarity alone could not cluster chemicals' potency, and in vitro models consistently ranked high in recursive feature elimination. This allows reducing the number of tests included in an ITS. Next, we analyzed with a hidden Markov model that takes advantage of an intrinsic inter-relationship among the local lymph node assay classes, i.e. the monotonous connection between local lymph node assay and dose. The dose-informed random forest/hidden Markov model was superior to the dose-naive random forest model on all data sets. Although balanced accuracy improvement may seem small, this obscures the actual improvement in misclassifications as the dose-informed hidden Markov model strongly reduced " false-negatives" (i.e. extreme sensitizers as non-sensitizer) on all data sets. PMID:26046447

  5. Chernobyl doses. Volume 1. Analysis of forest canopy radiation response from multispectral imagery and the relationship to doses. Technical report, 29 July 1987-30 September 1993

    SciTech Connect

    McClennan, G.E.; Anno, G.H.; Whicker, F.W.

    1994-09-01

    This volume of the report Chernobyl Doses presents details of a new, quantitative method for remotely sensing ionizing radiation dose to vegetation. Analysis of Landsat imagery of the area within a few kilometers of the Chernobyl nuclear reactor station provides maps of radiation dose to pine forest canopy resulting from the accident of April 26, 1986. Detection of the first date of significant, persistent deviation from normal of the spectral reflectance signature of pine foliage produces contours of radiation dose in the 20 to 80 Gy range extending up to 4 km from the site of the reactor explosion. The effective duration of exposure for the pine foliage is about 3 weeks. For this exposure time, the LD50 of Pinus sylvestris (Scotch pine) is about 23 Gy. The practical lower dose limit for the remote detection of radiation dose to pine foliage with the Landsat Thematic Mapper is about 5 Gy or 1/4 of the LD50.

  6. Dose-Response Relationship between Cumulative Occupational Lead Exposure and the Associated Health Damages: A 20-Year Cohort Study of a Smelter in China

    PubMed Central

    Wu, Yue; Gu, Jun-Ming; Huang, Yun; Duan, Yan-Ying; Huang, Rui-Xue; Hu, Jian-An

    2016-01-01

    Long-term airborne lead exposure, even below official occupational limits, has been found to cause lead poisoning at higher frequencies than expected, which suggests that China’s existing occupational exposure limits should be reexamined. A retrospective cohort study was conducted on 1832 smelting workers from 1988 to 2008 in China. These were individuals who entered the plant and came into continuous contact with lead at work for longer than 3 months. The dose-response relationship between occupational cumulative lead exposure and lead poisoning, abnormal blood lead, urinary lead and erythrocyte zinc protoporphyrin (ZPP) were analyzed and the benchmark dose lower bound confidence limits (BMDLs) were calculated. Statistically significant positive correlations were found between cumulative lead dust and lead fumes exposures and workplace seniority, blood lead, urinary lead and ZPP values. A dose-response relationship was observed between cumulative lead dust or lead fumes exposure and lead poisoning (p < 0.01). The BMDLs of the cumulative occupational lead dust and fumes doses were 0.68 mg-year/m3 and 0.30 mg-year/m3 for lead poisoning, respectively. The BMDLs of workplace airborne lead concentrations associated with lead poisoning were 0.02 mg/m3 and 0.01 mg/m3 for occupational exposure lead dust and lead fume, respectively. In conclusion, BMDLs for airborne lead were lower than occupational exposure limits, suggesting that the occupational lead exposure limits need re-examination and adjustment. Occupational cumulative exposure limits (OCELs) should be established to better prevent occupational lead poisoning. PMID:26999177

  7. Dose-Response Relationship between Cumulative Occupational Lead Exposure and the Associated Health Damages: A 20-Year Cohort Study of a Smelter in China.

    PubMed

    Wu, Yue; Gu, Jun-Ming; Huang, Yun; Duan, Yan-Ying; Huang, Rui-Xue; Hu, Jian-An

    2016-03-01

    Long-term airborne lead exposure, even below official occupational limits, has been found to cause lead poisoning at higher frequencies than expected, which suggests that China's existing occupational exposure limits should be reexamined. A retrospective cohort study was conducted on 1832 smelting workers from 1988 to 2008 in China. These were individuals who entered the plant and came into continuous contact with lead at work for longer than 3 months. The dose-response relationship between occupational cumulative lead exposure and lead poisoning, abnormal blood lead, urinary lead and erythrocyte zinc protoporphyrin (ZPP) were analyzed and the benchmark dose lower bound confidence limits (BMDLs) were calculated. Statistically significant positive correlations were found between cumulative lead dust and lead fumes exposures and workplace seniority, blood lead, urinary lead and ZPP values. A dose-response relationship was observed between cumulative lead dust or lead fumes exposure and lead poisoning (p < 0.01). The BMDLs of the cumulative occupational lead dust and fumes doses were 0.68 mg-year/m³ and 0.30 mg-year/m³ for lead poisoning, respectively. The BMDLs of workplace airborne lead concentrations associated with lead poisoning were 0.02 mg/m³ and 0.01 mg/m³ for occupational exposure lead dust and lead fume, respectively. In conclusion, BMDLs for airborne lead were lower than occupational exposure limits, suggesting that the occupational lead exposure limits need re-examination and adjustment. Occupational cumulative exposure limits (OCELs) should be established to better prevent occupational lead poisoning. PMID:26999177

  8. DOSE-RESPONSE RELATIONSHIPS FOR MOLECULAR ALTERATIONS INDUCED BY B[ A ]P IN STRAIN A/J MOUSE LUNG

    EPA Science Inventory

    Benzo[a]pyrene (B[a]P) induces tumors in rodents at doses much higher than those found in the environment. Current cancer risk assessment of B[a]P assumes that the risk posed by low level exposure to B[a]P is linear with respect to dose. We have measur...

  9. No evident dose-response relationship between cellular ROS level and its cytotoxicity--a paradoxical issue in ROS-based cancer therapy.

    PubMed

    Zhu, Chunpeng; Hu, Wei; Wu, Hao; Hu, Xun

    2014-01-01

    Targeting cancer via ROS-based mechanism has been proposed as a radical therapeutic approach. Cancer cells exhibit higher endogenous oxidative stress than normal cells and pharmacological ROS insults via either enhancing ROS production or inhibiting ROS-scavenging activity can selectively kill cancer cells. In this study, we randomly chose 4 cancer cell lines and primary colon or rectal cancer cells from 4 patients to test the hypothesis and obtained following paradoxical results: while piperlongumin (PL) and β-phenylethyl isothiocyanate (PEITC), 2 well-defined ROS-based anticancer agents, induced an increase of cellular ROS and killed effectively the tested cells, lactic acidosis (LA), a common tumor environmental factor that plays multifaceted roles in promoting cancer progression, induced a much higher ROS level in the tested cancer cells than PL and PEITC, but spared them; L-buthionine sulfoximine (L-BSO, 20 μM) depleted cellular GSH more effectively and increased higher ROS level than PL or PEITC but permitted progressive growth of the tested cancer cells. No evident dose-response relationship between cellular ROS level and cytotoxicity was observed. If ROS is the effecter, it should obey the fundamental therapeutic principle - the dose-response relationship. This is a major concern. PMID:24848642

  10. Dose-response relationships between plasma adrenocorticotropin (ACTH), cortisol, aldosterone, and 18-hydroxycorticosterone after injection of ACTH-(1-39) or human corticotropin-releasing hormone in man.

    PubMed

    Oelkers, W; Boelke, T; Bähr, V

    1988-01-01

    The effects of sc injections (at 1500 h) of increasing amounts of synthetic human ACTH-(1-39) (1.25-30 micrograms) on plasma ACTH, cortisol, aldosterone, and 18-hydroxycorticosterone were compared with those of iv injections of 30 and 100 micrograms synthetic human CRH in nine normal men. Five micrograms of ACTH, sc, was the lowest dose that significantly increased plasma levels of the three steroids. CRH (30 micrograms, iv) increased plasma cortisol and 18-hydroxycorticosterone, but not aldosterone, while 100 micrograms CRH also raised aldosterone secretion. The dose-response curve (peak plasma ACTH level vs. maximum increment of plasma cortisol within the first hour) was initially very steep. Plasma ACTH levels between 50 and 60 ng/L (11-13 pmol/L) stimulated cortisol to almost 80% of the maximal increment obtained with plasma ACTH levels above 300 ng/L (greater than 66 pmol/L). This dose-response relationship is similar to that found in clinical tests of the pituitary-adrenal axis (insulin test, metyrapone test). The effects of plasma ACTH released by CRH on cortisol secretion were not significantly different from those of injected ACTH. Our results argue against the hypothesis that the effect of CRH on steroid secretion is mediated or modulated by POMC-derived peptides other than ACTH. PMID:2826525

  11. DOSE-RESPONSE Relationships Between Whole-Body Vibration and Lumbar Disk DISEASE—A Field Study on 388 Drivers of Different Vehicles

    NASA Astrophysics Data System (ADS)

    Schwarze, S.; Notbohm, G.; Dupuis, H.; Hartung, E.

    1998-08-01

    In a longitudinal study, the dose-response relationships between long term occupational exposure to whole-body vibration and degenerative processes in the lumbar spine caused by the lumbar disks were examined. From 1990 to 1992, 388 vibration-exposed workers from different driving jobs were examined medically and by lumbar X-ray. For each individual, a history of all exposure conditions was recorded, and a cumulative vibration dose was calculated allowing comparisons between groups of low, middle, and high intensity of exposure. 310 subjects were selected for a follow-up four years later, of whom 90·6% (n=281) agreed to participate. In comparing the exposure groups, the results indicate that the limit value ofazw(8h)=0·8 m/s2should be reviewed. The best fit between the lifelong vibration dose and the occurrence of a lumbar syndrome was obtained by applying a daily reference ofazw(8h)=0·6 ms2as a limit value. The results became more distinct still when only those subjects were included in the statistical analysis who had had no lumbar symptoms up to the end of the first year of exposure. The prevalence of lumbar syndrome is 1·55 times higher in the highly exposed group when compared to the reference group with low exposure (CI95%=1·24/1·95). Calculating the cumulative incidence of new cases of lumbar syndrome in the follow-up period yields a relative risk ofRRMH=1·37 (CI95%=0·86/2·17) for the highly exposed group. It is concluded that the limit value for the calculation of an individual lifelong vibration dose should be based on a daily reference exposure ofazw(8h)=0·6 m/s2. With increasing dose it is more and more probable that cases of lumbar syndrome are caused by exposure to vibration.

  12. Nonlinear dose-response relationship between radon exposure and the risk of lung cancer: evidence from a meta-analysis of published observational studies.

    PubMed

    Duan, Peng; Quan, Chao; Hu, Chunhui; Zhang, Jicai; Xie, Fei; Hu, Xiuxue; Yu, Zongtao; Gao, Bo; Liu, Zhixiang; Zheng, Hong; Liu, Changjiang; Wang, Chengmin; Yu, Tingting; Qi, Suqin; Fu, Wenjuan; Kourouma, Ansoumane; Yang, Kedi

    2015-07-01

    Although radon exposure (RE) has been confirmed to increase the risk of lung cancer (LC), questions remain about the shape of the dose-response relationship between RE and the risk of LC. We carried out a dose-response meta-analysis to investigate and quantify the potential dose-response association between residential and occupational exposure to radon and the risk of LC. All cohort and case-control studies published in English and Chinese on Embase, PubMed, and China National Knowledge Infrastructure (CNKI) digital databases through November 2013 were identified systematically. We extracted effect measures (relative risk, odds ratio, standardized mortality ratio, standardized incidence ratio, or standardized rate ratio) from individual studies to generate pooled results using meta-analysis approaches. We derived meta-analytic estimates using random-effects models taking into account the correlation between estimates. Restricted cubic splines and generalized least-squares regression methods were used to model a potential curvilinear relationship and to carry out a dose-response meta-analysis. Stratified analysis, sensitivity analysis, and assessment of bias were performed in our meta-analysis. Sixty publications fulfilling the inclusion criteria for this meta-analysis were finally included. Occupational RE was associated with LC [risk ratio 1.86, 95% confidence interval (CI)=1.67-2.09; I²=92.2%; 27 prospective studies], for pooled risk estimate of the: standardized mortality ratio [2.00 (95% CI=1.82-2.32)]; standardized incidence ratio [1.45 (95% CI=1.20-1.74)]; relative risk [2.10 (95% CI=1.64-2.69)]. In a subgroup analysis of uranium miners and residents exposed to occupational uranium, the summary risk was 2.23 (95% CI=1.86-2.68) and 1.23 (95% CI=1.05-1.44). The overall meta-analysis showed evidence of a nonlinear association between RE and the risk of LC (P(nonlinearity)<0.014); in addition, the point value of residential radon also improved the results

  13. Dose response signal detection under model uncertainty.

    PubMed

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

    2015-12-01

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

  14. 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

  15. A Dose-Response Relationship between Organic Mercury Exposure from Thimerosal-Containing Vaccines and Neurodevelopmental Disorders

    PubMed Central

    Geier, David A.; Hooker, Brian S.; Kern, Janet K.; King, Paul G.; Sykes, Lisa K.; Geier, Mark R.

    2014-01-01

    A hypothesis testing case-control study evaluated concerns about the toxic effects of organic-mercury (Hg) exposure from thimerosal-containing (49.55% Hg by weight) vaccines on the risk of neurodevelopmental disorders (NDs). Automated medical records were examined to identify cases and controls enrolled from their date-of-birth (1991–2000) in the Vaccine Safety Datalink (VSD) project. ND cases were diagnosed with pervasive developmental disorder (PDD), specific developmental delay, tic disorder or hyperkinetic syndrome of childhood. In addition, putative non-thimerosal-related outcomes of febrile seizure, failure to thrive and cerebral degenerations were examined. The cumulative total dose of Hg exposure from thimerosal-containing hepatitis B vaccine (T-HBV) administered within the first six months of life was calculated. On a per microgram of organic-Hg basis, PDD (odds ratio (OR) = 1.054), specific developmental delay (OR = 1.035), tic disorder (OR = 1.034) and hyperkinetic syndrome of childhood (OR = 1.05) cases were significantly more likely than controls to receive increased organic-Hg exposure. By contrast, none of the non-thimerosal related outcomes were significantly more likely than the controls to have received increased organic-Hg exposure. Routine childhood vaccination may be an important public health tool to reduce infectious disease-associated morbidity/mortality, but the present study significantly associates organic-Hg exposure from T-HBV with an increased risk of an ND diagnosis. PMID:25198681

  16. A dose-response relationship between organic mercury exposure from thimerosal-containing vaccines and neurodevelopmental disorders.

    PubMed

    Geier, David A; Hooker, Brian S; Kern, Janet K; King, Paul G; Sykes, Lisa K; Geier, Mark R

    2014-09-01

    A hypothesis testing case-control study evaluated concerns about the toxic effects of organic-mercury (Hg) exposure from thimerosal-containing (49.55% Hg by weight) vaccines on the risk of neurodevelopmental disorders (NDs). Automated medical records were examined to identify cases and controls enrolled from their date-of-birth (1991-2000) in the Vaccine Safety Datalink (VSD) project. ND cases were diagnosed with pervasive developmental disorder (PDD), specific developmental delay, tic disorder or hyperkinetic syndrome of childhood. In addition, putative non-thimerosal-related outcomes of febrile seizure, failure to thrive and cerebral degenerations were examined. The cumulative total dose of Hg exposure from thimerosal-containing hepatitis B vaccine (T-HBV) administered within the first six months of life was calculated. On a per microgram of organic-Hg basis, PDD (odds ratio (OR) = 1.054), specific developmental delay (OR = 1.035), tic disorder (OR = 1.034) and hyperkinetic syndrome of childhood (OR = 1.05) cases were significantly more likely than controls to receive increased organic-Hg exposure. By contrast, none of the non-thimerosal related outcomes were significantly more likely than the controls to have received increased organic-Hg exposure. Routine childhood vaccination may be an important public health tool to reduce infectious disease-associated morbidity/mortality, but the present study significantly associates organic-Hg exposure from T-HBV with an increased risk of an ND diagnosis. PMID:25198681

  17. Evidence of a Non-Linear Dose-Response Relationship between Training Load and Stress Markers in Elite Female Futsal Players

    PubMed Central

    Milanez, Vinicius F.; Ramos, Solange P.; Okuno, Nilo M.; Boullosa, Daniel A.; Nakamura, Fabio Y.

    2014-01-01

    The aim of this study was: to describe typical training load (TL) carried out by a professional female futsal team for a period of 5 weeks; and to verify the relationship between TL, stress symptoms, salivary secretory immunoglobulin A (SIgA) levels, and symptoms of upper respiratory infections (URI). Over 45 sessions, the TL of the athletes was monitored daily by means of session-RPE method during the in-season period prior to the main national competition. Stress symptoms were measured weekly by means of the “Daily Analysis of Life Demands in Athletes Questionnaire” (DALDA), SIgA levels, and by symptoms of URI by the “Wisconsin Upper Respiratory Symptom Survey-21” (WURSS). There was a significant increase in TL, monotony, and training strain in week 3, with a concomitant and significant reduction in percentage variation (Δ%) of SIgA concentration and secretion rate (p < 0.05). Additionally, a second order regression model showed a high goodness of fit (R2 = 0.64 - 0.89) between TL and strain with SIgA concentration, secretion rate, and “worse than normal” responses of stress symptoms from the questionnaire. In conclusion, a link between TL and SIgA levels, and stress symptoms in female futsal players was evident in a non linear fashion. There appears to be an optimal range of values of daily TL between ~343 and ~419 AU and strain between ~2639 and 3060 AU, because at levels below and above these values there was an increase in stress symptoms and above ~435 and ~3160 AU to TL and strain there were a decrease in SIgA levels. In contrast, symptoms of URI failed to demonstrate relationship with the variables studied. Key Points There is a dose-response relationship between SIgA levels and stress symptoms with TL. For the athletes of the present study, values of ~436 AU and ~3161 AU to TL and strain training would be desirable because higher values would decrease responses of SIgA levels. An optimal range of values of TL between ~336 and ~412 AU to TL

  18. Meta-analysis for deriving age- and gender-specific dose-response relationships between urinary cadmium concentration and {beta} {sub 2}-microglobulinuria under environmental exposure

    SciTech Connect

    Gamo, Masashi . E-mail: masashi-gamo@aist.go.jp; Ono, Kyoko; Nakanishi, Junko

    2006-05-15

    A meta-analysis was conducted to derive age- and gender-specific dose-response relationships between urinary cadmium (Cd) concentration and {beta} {sub 2}-microglobulinuria ({beta}2MG-uria) under environmental exposure. {beta}2MG-uria was defined by a cutoff point of 1000 {mu}g {beta} {sub 2}-microglobulin/g creatinine. We proposed a model for describing the relationships among the interindividual variabilities in urinary Cd concentration, the ratio of Cd concentrations in the target organ and in urine, and the threshold Cd concentration in the target organ. The parameters in the model were determined so that good agreement might be achieved between the prevalence rates of {beta}2MG-uria reported in the literature and those estimated by the model. In this analysis, only the data from the literature on populations environmentally exposed to Cd were used. Using the model and estimated parameters, the prevalence rate of {beta}2MG-uria can be estimated for an age- and gender-specific subpopulation for which the distribution of urinary Cd concentrations is known. The maximum permissible level of urinary Cd concentration was defined as the maximum geometric mean of the urinary Cd concentration in an age- and gender-specific subpopulation that would not result in a statistically significant increase in the prevalence rate of {beta}2MG-uria. This was estimated to be approximately 3 {mu}g/g creatinine for a population in a small geographical area and approximately 2 {mu}g/g creatinine for a nationwide population.

  19. RELATIONSHIP BETWEEN SERUM CHOLINESTERASE ACTIVITY AND THE CHANGE IN BODY TEMPERATURE AND MOTOR ACTIVITY IN THE RAT: A DOSE RESPONSE STUDY OF DIISOPROPYL FLUOROPHATE (DFP)

    EPA Science Inventory

    Risk assessment of the neurotoxicology of organophosphate (OP) pesticides calls for a thorough understanding of the relationship between tissue cholinesterase (ChE) activity and changes in behavioral and autonomic responses to OP treatment. To address this issue, motor activity, ...

  20. mFISH analysis of chromosome aberrations induced in vitro by α-particle radiation: examination of dose-response relationships.

    PubMed

    Curwen, Gillian B; Tawn, E Janet; Cadwell, Kevin K; Guyatt, Laura; Thompson, James; Hill, Mark A

    2012-11-01

    A multicolored FISH (mFISH) technique was used to characterize the cytogenetic damage associated with exposure to α-particle radiation with particular emphasis on the quality and quantity that is likely to be transmitted through cell division to descendant cells. Peripheral blood lymphocytes were irradiated in vitro with (238)Pu α particles with a range of mean doses up to 936 mGy and were cultured for 47 h. The dose responses for total aberrant cells, stable and unstable cells, and cells with one simple chromosome aberration and multiple chromosome aberrations were predominantly linear for doses that resulted in cell nuclei receiving a single α-particle traversal. However, there was a decrease per unit dose in aberrant cells of all types at higher doses because of cells increasingly receiving multiple traversals. The proportion of radiation-induced aberrant cells containing multiple aberrations ranged from 48 to 74% with little evidence of dose dependency. Ninety-one percent of all cells with multiple aberrations were classified as unstable. Resolving the chromosome rearrangements into simple categories resulted in a linear dose response for dicentrics of 24.9 ± 3.3 × 10(-2) per Gy. The predominant aberration in stable transmissible cells was a single translocation with a dose response for predominantly single hit cell nuclei of 4.1 ± 1.3 × 10(-2) per Gy. Thus, translocations are the most likely aberration to be observed in peripheral blood lymphocytes from individuals with incorporated α-emitting radionuclides resulting in long-term chronic exposure. PMID:23083107

  1. Implicit dose-response curves.

    PubMed

    Pérez Millán, Mercedes; Dickenstein, Alicia

    2015-06-01

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

  2. Behavioral and electrophysiological dose-response relationships in adult western corn rootworm (Diabrotica virgifera virgifera LeConte) for host pollen amino acids.

    PubMed

    Hollister, Benedict; Mullin, Christopher A.

    1998-05-01

    A strong correlation is shown between taste cell inputs and phagostimulatory outputs with predominant dietary pollen amino acids for western corn rootworm, Diabrotica virgifera virgifera. Behavioral and electrophysiological dose-response profiles in adult beetles are presented for five major free amino acids in host pollens. Differential responses were found with strongest phagostimulation and sensory response elicited by L-alanine and L-serine, followed in order by L-proline and beta-alanine. gamma-Aminobutyric acid gave the weakest and most sporadic response. ED(50) values for phagostimulation and chemosensory input were 28.3nmol/disk and 13mM, respectively, for L-alanine and 17nmol/disk and 11mM, respectively, for serine. Threshold values for the responses were approximately 1-2mM. These behavioral and chemosensory dose-response ranges correspond closely to levels of free amino acids present in host plant pollens. Use of these response values in development of a pollen chemosensory code for western corn rootworm feeding is discussed. PMID:12770166

  3. 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.

  4. The Importance of Body Weight for the Dose Response Relationship of Oral Vitamin D Supplementation and Serum 25-Hydroxyvitamin D in Healthy Volunteers

    PubMed Central

    Ekwaru, John Paul; Zwicker, Jennifer D.; Holick, Michael F.; Giovannucci, Edward; Veugelers, Paul J.

    2014-01-01

    Unlike vitamin D recommendations by the Institute of Medicine, the Clinical Practice Guidelines by the Endocrine Society acknowledge body weight differentials and recommend obese subjects be given two to three times more vitamin D to satisfy their body's vitamin D requirement. However, the Endocrine Society also acknowledges that there are no good studies that clearly justify this. In this study we examined the combined effect of vitamin D supplementation and body weight on serum 25-hydroxyvitamin (25(OH)D) and serum calcium in healthy volunteers. We analyzed 22,214 recordings of vitamin D supplement use and serum 25(OH)D from 17,614 healthy adult volunteers participating in a preventive health program. This program encourages the use of vitamin D supplementation and monitors its use and serum 25(OH)D and serum calcium levels. Participants reported vitamin D supplementation ranging from 0 to 55,000 IU per day and had serum 25(OH)D levels ranging from 10.1 to 394 nmol/L. The dose response relationship between vitamin D supplementation and serum 25(OH)D followed an exponential curve. On average, serum 25(OH)D increased by 12.0 nmol/L per 1,000 IU in the supplementation interval of 0 to 1,000 IU per day and by 1.1 nmol/L per 1,000 IU in the supplementation interval of 15,000 to 20,000 IU per day. BMI, relative to absolute body weight, was found to be the better determinant of 25(OH)D. Relative to normal weight subjects, obese and overweight participants had serum 25(OH)D that were on average 19.8 nmol/L and 8.0 nmol/L lower, respectively (P<0.001). We did not observe any increase in the risk for hypercalcemia with increasing vitamin D supplementation. We recommend vitamin D supplementation be 2 to 3 times higher for obese subjects and 1.5 times higher for overweight subjects relative to normal weight subjects. This observational study provides body weight specific recommendations to achieve 25(OH)D targets. PMID:25372709

  5. 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

  6. 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

  7. Linear Versus Non-Linear Dose-Response Relationship Between Prenatal Alcohol Exposure and Meconium Concentration of Nine Different Fatty Acid Ethyl Esters.

    PubMed

    Yang, J Y; Kwak, H S; Han, J Y; Choi, J S; Ahn, H K; Oh, Y J; Velázquez-Armenta, E Y; Nava-Ocampo, A A

    2015-01-01

    Presence of individual fatty acid ethyl esters (FAEEs) in meconium is considered to be a reliable biomarker of prenatal alcohol exposure, and their concentration has been found to be linearly associated with poor postnatal development, supporting the widely extended idea that ethanol is a non-threshold teratogen. However, a growing number of epidemiological studies have consistently found a lack of adverse short- and long-term fetal outcomes at low exposure levels. We therefore aimed to investigate the relationship between the concentration of individual FAEEs and prenatal alcohol exposure in meconium samples collected within the first 6 to 12?h after birth from 182 babies born to abstainer mothers and from 54 babies born to women who self-reported either light or moderate alcohol ingestion in the second or third trimester of pregnancy. In most cases, the individual FAEE concentrations were negligible and not significantly different (P >0.05) between exposed and control babies. The concentrations appeared to increase linearly with the dose only in the few babies born to mothers who reported >3 drinks/week. These results provide evidence that the correlation between prenatal alcohol exposure and individual FAEE concentrations in meconium is non-linear shape, with a threshold probably at 3 drinks/week. PMID:26691866

  8. 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

  9. 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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  11. Realizing autonomy in responsive relationships

    PubMed Central

    Houtepen, Rob; Spreeuwenberg, Cor; Widdershoven, Guy

    2010-01-01

    The goal of this article is to augment the ethical discussion among nurses with the findings from empirical research on autonomy of older adults with type 2 diabetes mellitus. There are many factors influencing autonomy. These include: health conditions, treatment, knowledge, experience and skills, personal approach as well as familial patterns, type of relationship, life history and social context. Fifteen older adults with type 2 diabetes mellitus were interviewed in a nurse-led diabetes clinic. These participants perceive three processes which support autonomy in responsive relationships: preserving patterns of concern and interaction, nurturing collaborative responsibilities and being closely engaged in trustful and helpful family relations. People with diabetes realize autonomy in various responsive relationships in their unique life context. Next, we performed a literature review of care ethics and caring in nursing with regard to relational autonomy. We classified the literature in five strands of care: attitude-oriented, dialogue-oriented, activity-oriented, relationship-oriented and life-oriented. According to our respondents, autonomy in responsive relationships is fostered when patient, nurses, professionals of the health team and family members carry out care activities supported by a relational attitude of care. They can best realize autonomy in relationships with others when several essential aspects of care and caring are present in their lives. Therefore, we advocate a comprehensive approach to care and caring. PMID:20339930

  12. 5-ASA Dose-Response

    PubMed Central

    Katz, Seymour; Lichtenstein, Gary R; Safdi, Michael A

    2010-01-01

    Mesalamine (5-aminosalicylic acid; 5-ASA) represents the cornerstone of first-line therapy for mild-to-moderate ulcerative colitis (UC). Current guidelines suggest that the combination of oral and rectal therapies provide optimal symptom resolution and effectively maintain remission in the majority of these patients. Although effective, most oral 5-ASA formulations have a high pill burden and rectal therapies are associated with low adherence. Recent research has examined patterns of compliance, as well as the efficacy of different dose levels of 5-ASA in terms of symptom resolution, the maintenance of remission, and improvements in quality of life. The ASCEND I, II, and III trials found that doses of 4.8 g/day are more effective than 2.4 g/day doses in patients with moderate disease, those with previous steroid use, and those with a history of multiple medications. The benefits of effective long-term 5-ASA therapy include the avoidance of more costly and potentially toxic drugs (such as corticosteroids and biologic therapies), as well as improvements in quality of life, reductions in the need for future colectomy, and a lower risk of developing colorectal cancer. PMID:20567558

  13. Deviation from additivity in mixture toxicity: relevance of nonlinear dose-response relationships and cell line differences in genotoxicity assays with combinations of chemical mutagens and gamma-radiation.

    PubMed Central

    Lutz, Werner K; Vamvakas, Spyros; Kopp-Schneider, Annette; Schlatter, Josef; Stopper, Helga

    2002-01-01

    Sublinear dose-response relationships are often seen in toxicity testing, particularly with bioassays for carcinogenicity. This is the result of a superimposition of various effects that modulate and contribute to the process of cancer formation. Examples are saturation of detoxification pathways or DNA repair with increasing dose, or regenerative hyperplasia and indirect DNA damage as a consequence of high-dose cytotoxicity and cell death. The response to a combination treatment can appear to be supra-additive, although it is in fact dose-additive along a sublinear dose-response curve for the single agents. Because environmental exposure of humans is usually in a low-dose range and deviation from linearity is less likely at the low-dose end, combination effects should be tested at the lowest observable effect levels (LOEL) of the components. This principle has been applied to combinations of genotoxic agents in various cellular models. For statistical analysis, all experiments were analyzed for deviation from additivity with an n-factor analysis of variance with an interaction term, n being the number of components tested in combination. Benzo[a]pyrene, benz[a]anthracene, and dibenz[a,c]anthracene were tested at the LOEL, separately and in combination, for the induction of revertants in the Ames test, using Salmonella typhimurium TA100 and rat liver S9 fraction. Combined treatment produced no deviation from additivity. The induction of micronuclei in vitro was investigated with ionizing radiation from a 137Cs source and ethyl methanesulfonate. Mouse lymphoma L5178Y cells revealed a significant 40% supra-additive combination effect in an experiment based on three independent replicates for controls and single and combination treatments. On the other hand, two human lymphoblastoid cell lines (TK6 and WTK1) as well as a pilot study with human primary fibroblasts from fetal lung did not show deviation from additivity. Data derived from one cell line should therefore

  14. Relationship between dose and health effects

    SciTech Connect

    Kimbrough, R.D.

    1984-09-01

    The health effects produced by chemicals depend on the inherent toxicity of the chemical and the dose received by the exposed individual. Health effects are modified by genetic make-up, life style, nutrition, and interaction with other chemicals. In some situations it may be difficult to impossible to determine through epidemiologic studies whether exposure to chemicals (naturally occurring or synthetic) has caused harm. For all practical purposes, the risk associated with minuscule doses of most chemicals is negligible.

  15. Code System for Emergency Response Dose Assessment.

    Energy Science and Technology Software Center (ESTSC)

    2002-01-16

    Version: 00 A dose assessment model for emergency response applications. Dose pathways represented in the model are those that are most likely to be important during and immediately following a release (hours) rather than over an extended time frame (days or weeks). The doses computed include: external dose resulting from exposure to radiation emitted by radionuclides in the air and deposited on the ground, internal dose commitment resulting from inhalation, and total whole-body dose. Threemore » preprocessors are included. RSFPREP generates the MESORAD run specification (input) file, METWR creates the meteorological data file, and RELPREP prepares the release definition file. PRNT is a postprocessor for generating printer or screen-compatible output. All four programs run interactively. MESORAD was developed from version 2.0 of the MESOI atmospheric dispersion model (NESC 9862) retaining its modular nature.« less

  16. 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.

  17. Acute Administration of Clozapine and Risperidone Altered Dopamine Metabolism More in Rat Caudate than in Nucleus Accumbens: A Dose-Response Relationship

    PubMed Central

    Batool, Farhat; Haleem, Muhammad A.; Haleem, Darakhshan J.

    2010-01-01

    The present study compares the extrapyramidal and neurochemical effects of clozapine and risperidone in rat caudate (corpus striatum) and nucleus accumbens (ventral striatum) dose-dependently. Animals injected with clozapine (2.5, 5.0 and 10.0 mg/kg IP) or risperidone (1.0, 2.5 and 5.0 mg/kg IP) in acute were sacrificed 1 h later to collect brain samples. Extrapyramidal side effects (EPS) in terms of locomotor activity and catalepsy were monitored in each animal after the drug or vehicle administration. Maximum cataleptic potentials were found only at high doses of clozapine (10.0 mg/kg; 60%) and risperidone (5.0 mg/kg; 100%). Neurochemical estimations were carried out by HPLC-EC. Both drugs at all doses significantly (p<0.01) increased the concentration of homovanillic acid (HVA), a metabolite of DA, in the caudate nucleus and decreased in nucleus accumbens. Levels of Dihydroxyphenylacetic acid (DOPAC) significantly (p<0.01) increased in the caudate by clozapine administration and decreased in the nucleus accumbens by the administration of both drugs in a dose-dependent manner. 5-Hydroxyindoleacetic acid (5-HIAA), the predominant metabolite of serotonin significantly decreased in the caudate and nucleus accumbens in a similar fashion. Levels of tryptophan (TRP) were remained insignificant in caudate and nucleus accumbens by the injections of two drugs. In caudate, clozapine and risperidone administrations significantly (p<0.01) decreased HVA/DA ratio and increased DOPAC/DA ratio in nucleus accumbens at all doses. The findings suggest the evidence for DA/5-HT receptor interaction as an important link in the lower incidence of EPS. The possible role of serotonin1A receptors in the pathophysiology of schizophrenia is also discussed. PMID:21179339

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

    SciTech Connect

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

    2007-07-01

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

  19. 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.

  20. Heparin-induced platelet aggregation (H-IPA): dose/response relationship for two low molecular weight (LMW) heparin preparations (CY 216 and CY 222)

    SciTech Connect

    Brace, L.D.; Fareed, J.

    1986-03-01

    The authors have previously demonstrated that heparin and a LMW heparin derivative (PK 10169) causes platelet aggregation in a dose-dependent manner that can be inhibited by antagonists of the thromboxane pathway. Using fractions of these agents separated on the basis of molecular weight (MW) by gel permeation chromatography, the authors showed that H-IPA was directly dependent upon the MW of the agents tested. In order to further examine this MW dependence, the authors tested two other LMW heparin preparations, CY 216 and CY 222 and subfractions of these agents separated on the basis of MW. Citrate anticoagulated whole blood was drawn from drug-free normal healthy donors whose platelets aggregated when heparin was added to their platelet-rich plasma (PRP). PRP was prepared, various concentrations of the agents or their subfractions were added and aggregation was monitored for 40 minutes at 37/sup 0/C. The results demonstrate that like heparin and PK 10169, CY 216 and CY 222 caused platelet aggregation in a dose and MW dependent manner. Fractions with MW less than 2500 daltons caused aggregation only at concentrations exceeding the therapeutic range of the agents. The authors conclude that the ability to cause H-IPA is an inherent property of heparin and its fractions.

  1. Testosterone Dose-Response Relationships in Hysterectomized Women with and without Oophorectomy: Effects on Sexual Function, Body Composition, Muscle Performance and Physical Function in a Randomized Trial

    PubMed Central

    Huang, Grace; Basaria, Shehzad; Travison, Thomas G.; Ho, Matthew H.; Davda, Maithili; Mazer, Norman A.; Miciek, Renee; Knapp, Philip E.; Zhang, Anqi; Collins, Lauren; Ursino, Monica; Appleman, Erica; Dzekov, Connie; Stroh, Helene; Ouellette, Miranda; Rundell, Tyler; Baby, Merilyn; Bhatia, Narender N.; Khorram, Omid; Friedman, Theodore; Storer, Thomas W.; Bhasin, Shalender

    2015-01-01

    Objective To determine dose-dependent effects of testosterone on sexual function, body composition, muscle performance, and physical function in hysterectomized women with and without oophorectomy. Methods 71 menopausal women who previously underwent hysterectomy with or without oophorectomy with total testosterone<31ng/dl or free testosterone<3.5 pg/ml received a standardized transdermal estradiol regimen during the 12-week run-in period, and were then randomized to receive weekly IM injections of placebo, or 3, 6.25, 12.5 or 25 mg testosterone enanthate for 24 weeks. Total and free testosterone levels were measured by LC-MS/MS and equilibrium dialysis, respectively. The primary outcome was change in sexual function measured using Brief Index of Sexual Function (BISF-W); Secondary outcomes included changes in sexual activity, sexual distress, DeRogatis Inventory of Sexual Function, lean (LBM) and fat mass, muscle strength and power, and physical function. Results 71 women were randomized; five groups were similar at baseline. 62 women with analyzable data for the primary outcome were included in the final analysis. Mean on-treatment total testosterone concentrations were 19, 78, 102, 128 and 210ng/dl in the placebo, 3, 6.25, 12.5 and 25-mg groups, respectively. Changes in composite BISF-W scores, thoughts-desire, arousal, frequency of sexual activity, LBM, chest-press power and loaded stair-climb power were significantly related to increases in free testosterone concentrations; changes were significantly greater in women assigned to the 25-mg group when compared to placebo but not at the lower dose groups. Sexual activity increased by 2.7 encounters per week in 25-mg group. Frequency of androgenic adverse events was low. Conclusion Testosterone administration in hysterectomized women with and without oophorectomy for 24-weeks was associated with dose and concentration-dependent gains in several domains of sexual function, LBM, chest-press power and loaded stair

  2. Dichloroacetate toxicokinetics and disruption of tyrosine catabolism in B6C3F1 mice: dose-response relationships and age as a modifying factor

    SciTech Connect

    Schultz, Irv R. ); Merdink, James L.; Gonzalez-Leon, Alberto; Bull, R J.

    2002-01-01

    Dichloroacetate (DCA) is a well established rodent carcinogen commonly found in municipal drinking water supplies. Previous toxicokinetic studies have established that elimination of DCA is controlled by liver metabolism. DCA metabolism occurs by the cytosolic enzyme glutathione-S-transferase-zeta (GSTz). An important feature of the GSTz pathway is the autoinhibition of metabolism due to suicide inactivation of GSTz by DCA resulting in a direct reduction in GSTz activity. GSTz is identical to a key tyrosine catabolism enzyme known as maleylacetoacetate isomerase (MAAI; EC 5.3.1.2). In the tyrosine metabolism pathway, GSTz plays a critical role in catalyzing the isomerization of maleylacetoacetate to fumarylacetoacetate. Disruption of tyrosine catabolism has been linked to increased cancer risk in humans. We studied the elimination of i.v. doses of DCA to juvenile (8 week) and senescent (60 week) mice previously treated with DCA in their drinking water for 2 or 54 weeks. The diurnal change in blood concentrations of DCA was also monitored in mice exposed to three different drinking water concentrations of DCA (2.0, 0.5 and 0.05 g/L). Additional experiments measured the in-vitro metabolism of DCA in liver homogenates prepared from treated mice given various recovery times following treatment. The MAAI activity was also measured in liver cytosol obtained from treated mice. Results indicate juvenile mice were the most sensitive to changes in DCA elimination after drinking water treatment. MAAI activity was reduced up to 80% in liver cytosol from treated mice. These results indicate that inactivation and re-synthesis of GSTz is a highly dynamic process and is supportive of the hypothesis that decreased MAAI activity is a contributing factor in the carcinogenesis of DCA.

  3. BEHAVIRORAL EFFECTS OF MICROWAVES: RELATIONSHIP OF TOTAL DOSE AND DOSE RATE

    EPA Science Inventory

    The goal of the research was to compare the relationship of whole body averaged specific absorption rate (SAR) and specific absorption (SA) to determine whether dose rate or dose was the better predictor of biological effects. Sperm positive Long-Evans female rats were exposed to...

  4. Inferring mechanisms from dose-response curves

    PubMed Central

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

    2011-01-01

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

  5. Creating good relationships: responsiveness, relationship quality, and interpersonal goals.

    PubMed

    Canevello, Amy; Crocker, Jennifer

    2010-07-01

    Perceived partner responsiveness is a core feature of close, satisfying relationships. But how does responsiveness originate? Can people create relationships characterized by high responsiveness and, consequently, higher quality relationships? The authors suggest that goals contribute to cycles of responsiveness between two people, improving relationship quality for both of them. The present studies examine (a) how interpersonal goals initiate responsiveness processes in close relationships, (b) the self-perpetuating nature of these processes, and (c) how responsiveness evolves dynamically over time through both intrapersonal projection and reciprocal interpersonal relationship processes. In a semester-long study of 115 roommate dyads, actors' compassionate and self-image goals predicted a cycle of responsiveness between roommates, occurring within weeks and across the semester. In a 3-week study of 65 roommate dyads, actors' goals again predicted cycles of responsiveness between roommates, which then contributed to both actors' and partners' relationship quality. Results suggest that both projection and reciprocation of responsiveness associated with compassionate goals create upward spirals of responsiveness that ultimately enhance relationship quality for both people. PMID:20565187

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

    PubMed

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

    2005-01-01

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

  7. Fewer Doses of HPV Vaccine Result in Immune Response Similar to Three-Dose Regimen

    MedlinePlus

    ... Releases NCI News Note Fewer doses of HPV vaccine result in immune response similar to three-dose ... that two doses of a human papillomavirus (HPV) vaccine, trademarked as Cervarix, resulted in similar serum antibody ...

  8. Harderian Gland Tumorigenesis: Low-Dose and LET Response.

    PubMed

    Chang, Polly Y; Cucinotta, Francis A; Bjornstad, Kathleen A; Bakke, James; Rosen, Chris J; Du, Nicholas; Fairchild, David G; Cacao, Eliedonna; Blakely, Eleanor A

    2016-05-01

    Increased cancer risk remains a primary concern for travel into deep space and may preclude manned missions to Mars due to large uncertainties that currently exist in estimating cancer risk from the spectrum of radiations found in space with the very limited available human epidemiological radiation-induced cancer data. Existing data on human risk of cancer from X-ray and gamma-ray exposure must be scaled to the many types and fluences of radiations found in space using radiation quality factors and dose-rate modification factors, and assuming linearity of response since the shapes of the dose responses at low doses below 100 mSv are unknown. The goal of this work was to reduce uncertainties in the relative biological effect (RBE) and linear energy transfer (LET) relationship for space-relevant doses of charged-particle radiation-induced carcinogenesis. The historical data from the studies of Fry et al. and Alpen et al. for Harderian gland (HG) tumors in the female CB6F1 strain of mouse represent the most complete set of experimental observations, including dose dependence, available on a specific radiation-induced tumor in an experimental animal using heavy ion beams that are found in the cosmic radiation spectrum. However, these data lack complete information on low-dose responses below 0.1 Gy, and for chronic low-dose-rate exposures, and there are gaps in the LET region between 25 and 190 keV/μm. In this study, we used the historical HG tumorigenesis data as reference, and obtained HG tumor data for 260 MeV/u silicon (LET ∼70 keV/μm) and 1,000 MeV/u titanium (LET ∼100 keV/μm) to fill existing gaps of data in this LET range to improve our understanding of the dose-response curve at low doses, to test for deviations from linearity and to provide RBE estimates. Animals were also exposed to five daily fractions of 0.026 or 0.052 Gy of 1,000 MeV/u titanium ions to simulate chronic exposure, and HG tumorigenesis from this fractionated study were compared to the

  9. Radiological dose reconstruction for birds reconciles outcomes of Fukushima with knowledge of dose-effect relationships

    PubMed Central

    Garnier-Laplace, Jacqueline; Beaugelin-Seiller, Karine; Della-Vedova, Claire; Métivier, Jean-Michel; Ritz, Christian; Mousseau, Timothy A.; Pape Møller, Anders

    2015-01-01

    We reconstructed the radiological dose for birds observed at 300 census sites in the 50-km northwest area affected by the accident at the Fukushima Daiichi nuclear power plant over 2011–2014. Substituting the ambient dose rate measured at the census points (from 0.16 to 31 μGy h−1) with the dose rate reconstructed for adult birds of each species (from 0.3 to 97 μGy h−1), we confirmed that the overall bird abundance at Fukushima decreased with increasing total doses. This relationship was directly consistent with exposure levels found in the literature to induce physiological disturbances in birds. Among the 57 species constituting the observed bird community, we found that 90% were likely chronically exposed at a dose rate that could potentially affect their reproductive success. We quantified a loss of 22.6% of the total number of individuals per increment of one unit log10-tansformed total dose (in Gy), over the four-year post-accident period in the explored area. We estimated that a total dose of 0.55 Gy reduced by 50% the total number of birds in the study area over 2011–2014. The data also suggest a significant positive relationship between total dose and species diversity. PMID:26567770

  10. Radiological dose reconstruction for birds reconciles outcomes of Fukushima with knowledge of dose-effect relationships

    NASA Astrophysics Data System (ADS)

    Garnier-Laplace, Jacqueline; Beaugelin-Seiller, Karine; Della-Vedova, Claire; Métivier, Jean-Michel; Ritz, Christian; Mousseau, Timothy A.; Pape Møller, Anders

    2015-11-01

    We reconstructed the radiological dose for birds observed at 300 census sites in the 50-km northwest area affected by the accident at the Fukushima Daiichi nuclear power plant over 2011-2014. Substituting the ambient dose rate measured at the census points (from 0.16 to 31 μGy h-1) with the dose rate reconstructed for adult birds of each species (from 0.3 to 97 μGy h-1), we confirmed that the overall bird abundance at Fukushima decreased with increasing total doses. This relationship was directly consistent with exposure levels found in the literature to induce physiological disturbances in birds. Among the 57 species constituting the observed bird community, we found that 90% were likely chronically exposed at a dose rate that could potentially affect their reproductive success. We quantified a loss of 22.6% of the total number of individuals per increment of one unit log10-tansformed total dose (in Gy), over the four-year post-accident period in the explored area. We estimated that a total dose of 0.55 Gy reduced by 50% the total number of birds in the study area over 2011-2014. The data also suggest a significant positive relationship between total dose and species diversity.

  11. Radiological dose reconstruction for birds reconciles outcomes of Fukushima with knowledge of dose-effect relationships.

    PubMed

    Garnier-Laplace, Jacqueline; Beaugelin-Seiller, Karine; Della-Vedova, Claire; Métivier, Jean-Michel; Ritz, Christian; Mousseau, Timothy A; Møller, Anders Pape

    2015-01-01

    We reconstructed the radiological dose for birds observed at 300 census sites in the 50-km northwest area affected by the accident at the Fukushima Daiichi nuclear power plant over 2011-2014. Substituting the ambient dose rate measured at the census points (from 0.16 to 31 μGy h(-1)) with the dose rate reconstructed for adult birds of each species (from 0.3 to 97 μGy h(-1)), we confirmed that the overall bird abundance at Fukushima decreased with increasing total doses. This relationship was directly consistent with exposure levels found in the literature to induce physiological disturbances in birds. Among the 57 species constituting the observed bird community, we found that 90% were likely chronically exposed at a dose rate that could potentially affect their reproductive success. We quantified a loss of 22.6% of the total number of individuals per increment of one unit log10-tansformed total dose (in Gy), over the four-year post-accident period in the explored area. We estimated that a total dose of 0.55 Gy reduced by 50% the total number of birds in the study area over 2011-2014. The data also suggest a significant positive relationship between total dose and species diversity. PMID:26567770

  12. Influences of mechanical exposure biographies on physical capabilities of workers from automotive industry - a study on possible dose-response relationships and consequences for short and long term job rotation.

    PubMed

    Rademacher, Holger; Bruder, Ralph; Sinn-Behrendt, Andrea; Landau, Kurt

    2012-01-01

    This paper describes a field study in production areas of a vehicle manufacturing plant, where 106 male workers (aged from 20 to 63 years) were examined and interviewed by the authors. Aim of study was to identify relationships between specific physical worker capabilities and doses of mechanical exposures using self-developed standardized questionnaires as well as a battery of work-specific tests. The dependent variables are different "physical capabilities", classified using a five-point rating scale with regard to the grade of limitation of the respective capability. Independent variables are "age" and specific "mechanical exposures". Several exposures were combined and multiplied with their respective durations in order to determine doses on three different body regions - back, shoulder-neck and upper limbs. There are significant positive correlations between "age" and "dose of mechanical exposure on back/shoulder-neck/upper limbs region". The analysis of the relationship between dose of exposure and different capabilities to lift or reposition loads (with variable weight) shows weak significant correlations for all three body regions. Data analysis shows no significant correlations between any dose of mechanical exposure and capabilities to work in awkward body postures.These results should be considered in age management programs when scheduling future employee assignments to workplaces, especially for production systems where manual handling tasks are dominant. PMID:22317513

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

    PubMed

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

    2014-08-01

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

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

    PubMed

    Calabrese, Edward J

    2016-08-01

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

  15. 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…

  16. LINKING MOLECULAR EVENT TO CELLULAR RESPONSES AT LOW DOSE EXPOSURES

    EPA Science Inventory

    Defining low dose radiation cancer risks is limited by our ability to measure and directly correlate relevant cellular and molecular responses occurring at low dose and dose rate with tumor formation. This deficiency has led to conservative risk assessments based on low dose ext...

  17. Dose-Effect Relationship in Chemoradiotherapy for Locally Advanced Rectal Cancer: A Randomized Trial Comparing Two Radiation Doses

    SciTech Connect

    Jakobsen, Anders; Ploen, John; Vuong, Te; Appelt, Ane; Lindebjerg, Jan; Rafaelsen, Soren R.

    2012-11-15

    Purpose: Locally advanced rectal cancer represents a major therapeutic challenge. Preoperative chemoradiation therapy is considered standard, but little is known about the dose-effect relationship. The present study represents a dose-escalation phase III trial comparing 2 doses of radiation. Methods and Materials: The inclusion criteria were resectable T3 and T4 tumors with a circumferential margin of {<=}5 mm on magnetic resonance imaging. The patients were randomized to receive 50.4 Gy in 28 fractions to the tumor and pelvic lymph nodes (arm A) or the same treatment supplemented with an endorectal boost given as high-dose-rate brachytherapy (10 Gy in 2 fractions; arm B). Concomitant chemotherapy, uftoral 300 mg/m{sup 2} and L-leucovorin 22.5 mg/d, was added to both arms on treatment days. The primary endpoint was complete pathologic remission. The secondary endpoints included tumor response and rate of complete resection (R0). Results: The study included 248 patients. No significant difference was found in toxicity or surgical complications between the 2 groups. Based on intention to treat, no significant difference was found in the complete pathologic remission rate between the 2 arms (18% and 18%). The rate of R0 resection was different in T3 tumors (90% and 99%; P=.03). The same applied to the rate of major response (tumor regression grade, 1+2), 29% and 44%, respectively (P=.04). Conclusions: This first randomized trial comparing 2 radiation doses indicated that the higher dose increased the rate of major response by 50% in T3 tumors. The endorectal boost is feasible, with no significant increase in toxicity or surgical complications.

  18. 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

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

    PubMed Central

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

    1989-01-01

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

  20. Advanced Computational Approaches for Characterizing Stochastic Cellular Responses to Low Dose, Low Dose Rate Exposures

    SciTech Connect

    Scott, Bobby, R., Ph.D.

    2003-06-27

    applications of NEOTRANS2, indicate that nonlinear threshold-type, dose-response relationships for excess stochastic effects (problematic nonlethal mutations, neoplastic transformation) should be expected after exposure to low linear energy transfer (LET) gamma rays or gamma rays in combination with high-LET alpha radiation. Similar thresholds are expected for low-dose-rate low-LET beta irradiation. We attribute the thresholds to low-dose, low-LET radiation induced protection against spontaneous mutations and neoplastic transformations. The protection is presumed mainly to involve selective elimination of problematic cells via apoptosis. Low-dose, low-LET radiation is presumed to trigger wide-area cell signaling, which in turn leads to problematic bystander cells (e.g., mutants, neoplastically transformed cells) selectively undergoing apoptosis. Thus, this protective bystander effect leads to selective elimination of problematic cells (a tissue cleansing process in vivo). However, this protective bystander effects is a different process from low-dose stimulation of the immune system. Low-dose, low-LET radiation stimulation of the immune system may explain why thresholds for inducing excess cancer appear much larger (possibly more than 100-fold larger) than thresholds for inducing excess mutations and neoplastic transformations, when the dose rate is low. For ionizing radiation, the current risk assessment paradigm is such that the relative risk (RR) is always ¡Ý 1, no matter how small the dose. Our research results indicate that for low-dose or low-dose-rate, low-LET irradiation, RR < 1 may be more the rule than the exception. Directly tied to the current RR paradigm are the billion-dollar cleanup costs for radionuclide-contaminated DOE sites. Our research results suggest that continued use of the current RR paradigm for which RR ¡Ý 1 could cause more harm than benefit to society (e.g., by spreading unwarranted fear about phantom excess risks associated with low-dose low

  1. Renal dysfunction after total body irradiation: Dose-effect relationship

    SciTech Connect

    Kal, Henk B. . E-mail: H.B.Kal@UMCUtrecht.nl; Kempen-Harteveld, M. Loes van

    2006-07-15

    Purpose: Late complications related to total body irradiation (TBI) as part of the conditioning regimen for hematopoietic stem cell transplantation have been increasingly noted. We reviewed and compared the results of treatments with various TBI regimens and tried to derive a dose-effect relationship for the endpoint of late renal dysfunction. The aim was to find the tolerance dose for the kidney when TBI is performed. Methods and Materials: A literature search was performed using PubMed for articles reporting late renal dysfunction. For intercomparison, the various TBI regimens were normalized using the linear-quadratic model, and biologically effective doses (BEDs) were calculated. Results: Eleven reports were found describing the frequency of renal dysfunction after TBI. The frequency of renal dysfunction as a function of the BED was obtained. For BED >16 Gy an increase in the frequency of dysfunction was observed. Conclusions: The tolerance BED for kidney tissue undergoing TBI is about 16 Gy. This BED can be realized with highly fractionated TBI (e.g., 6 x 1.7 Gy or 9 x 1.2 Gy at dose rates >5 cGy/min). To prevent late renal dysfunction, the TBI regimens with BED values >16 Gy (almost all found in published reports) should be applied with appropriate shielding of the kidneys.

  2. Neonatal Outcomes and their Relationship to Maternal Buprenorphine Dose during Pregnancy

    PubMed Central

    Jones, Hendrée E.; Dengler, Erin; Garrison, Anna; O'Grady, Kevin E.; Seashore, Carl; Horton, Evette; Andringa, Kim; Jansson, Lauren M.; Thorp, John

    2014-01-01

    Background Buprenorphine pharmacotherapy for opioid-dependent pregnant women is associated with maternal and neonatal outcomes superior to untreated opioid dependence. However, the literature is inconsistent regarding the possible existence of a dose-response relationship between maternal buprenorphine dose and neonatal clinical outcomes. Methods The present secondary analysis study (1) examined the relationship between maternal buprenorphine dose at delivery and neonatal abstinence syndrome (NAS) peak score, estimated gestational age at delivery, Apgar scores at 1 and 5 minutes, neonatal head circumference, length, and weight at birth, amount of morphine needed to treat NAS, duration of NAS treatment, and duration of neonatal hospital stay; and (2) compared neonates who required pharmacotherapy for NAS to neonates who did not require such pharmacotherapy on these same outcomes, in 58 opioid-dependent pregnant women receiving buprenorphine as participants in a randomized clinical trial. Results (1) Analyses failed to provide evidence of a relationship between maternal buprenorphine dose at delivery and any of the 10 outcomes (all p-values>.48); and (2) significant mean differences between the untreated (n=31) and treated (n=27) for NAS groups were found for duration of neonatal hospital stay and NAS peak score (both p-values<.001). Conclusions (1) Findings failed to support the existence of a dose-response relationship between maternal buprenorphine dose at delivery and any of 10 neonatal clinical outcomes, including NAS severity; and (2) that infants treated for NAS had a higher mean NAS peak score and, spent a longer time in the hospital than did the group not treated for NAS is unsurprising. PMID:24290979

  3. UV dose-effect relationships and current protection exposure standards

    SciTech Connect

    Singh, M.S.; Campbell, G.W.

    1982-04-01

    In this paper we have attempted to quantify the health effects in man of uv-radiation exposure of wavelengths from 240 nm to 320 nm. Exposure to uv in this region could result in the formation of skin cancer or premature aging in man. The induction of cancer by uv radiation results from changes in genetic material. We have used the DNA action spectrum coupled with the uv skin cancer data available in the literature to derive the dose-effect relationships. The results are compared against the current uv protection standards.

  4. 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.

  5. 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.

  6. Oligodendroglial response to ionizing radiation: Dose and dose-rate response

    SciTech Connect

    Levy, R.P.

    1991-01-01

    An in vitro system using neuroglia from neonatal rat brain was developed to examining the morphologic, immunocytochemical and biochemical response of oligodendroglia to ionizing radiation. Following acute [gamma]-radiation at day-in-culture (DIC) 8, oligodendrocyte counts at DIC 14 were 55% to 65% of control values after 2 Gy, and 29% to 36% after 5 Gy. Counts increased to near-normal levels at DIC 21 in the 2 Gy group and to 75% of normal in the 5 Gy group. Myelin basic protein levels (MBP) at DIC 14 were 60% of control values after 2 Gy, and 40% after 5 Gy. At DIC 21, MBP after 2 Gy was 45% greater than that observed at DIC 14, but MBP, as a fraction of age-matched control values, dropped from 60% to 50%. Following 5 Gy, absolute MBP changed little between DIC 14 and DIC 21, but decreased from 40% to 25% of control cultures. It was concluded that oligodendrocytes in irradiated cultures had significantly lower functional capacity than did unirradiated controls. The response to split-dose irradiation indicated that nearly all sublethal damage in the oligodendrocyte population (and its precursors) was repaired within 3 h to 4 h. At DIC 14, the group irradiated in a single fraction had significantly lower oligodendrocyte counts than any group given split doses; all irradiated cultures had marked depression of MBP synthesis, but to significant differences referable to time interval between doses. At DIC 21, cultures irradiated at intervals of 0 h to 2 h had similar oligodendrocyte counts to one another, but these counts were significantly lower than in cultures irradiated at intervals of 4 h to 6 h; MBP levels remained depressed at DIC 21 for all irradiated cultures. The oligodendrocyte response to dose rate (0.03 to 1.97 Gy/min) was evaluated at DIC 14 and DIC 21. Exposure at 0.03 Gy/min suppressed oligodendrocyte counts at DIC 21 less than did higher dose rates in 5-Gy irradiated cultures.

  7. 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.

  8. Renal damage in the mouse: the response to very small doses per fraction

    SciTech Connect

    Joiner, M.C.; Johns, H.

    1988-05-01

    Experiments were undertaken to study the effect on the mouse kidney of repeated X-ray doses in the range 0.2 to 1.6 Gy per fraction and neutron doses in the range 0.05 to 0.25 Gy per fraction. A top-up design of experiment was used, so that additional graded doses of d(4)-Be neutrons (EN = 2.3 MeV) were given to bring the subthreshold damage produced by these treatments into the measurable range. This approach avoided the necessity to use a large number of fractions to study low doses per fraction. Renal damage was assessed using three methods: 51Cr-EDTA clearance, urine output, and hematocrit at 16-50 weeks postirradiation. The dose-response curves obtained were resolved best at 29 weeks. However, the results were also examined by fitting second-order polynomials to the data for response versus time postirradiation and using interpolated values from these functions at 29 weeks to construct dose-response curves. This method reduced slightly the variation in the dose-response data, but the interrelationship between the dose-response curves remained the same. The data were used to test the linear-quadratic (LQ) description of the underlying X-ray dose-fractionation relationship. The model fits well down to X-ray doses per fraction of approximately 1 Gy, but lower X-ray doses were more effective per gray than predicted by LQ, as seen previously in skin. This increased X-ray effectiveness and deviation from LQ are reflected directly in a decrease in the RBE of d(4)-Be neutrons relative to X-rays at low doses, since the underlying response to these neutrons is linear in this low-dose region.

  9. Methodology for Estimating Ingestion Dose for Emergency Response at SRS

    SciTech Connect

    Simpkins, A.A.

    2003-07-21

    At the Savannah River Site (SRS), emergency response computer models are used to estimate dose following releases of radioactive materials to the environment. Downwind air and ground concentrations and their associated doses from inhalation and ground shine pathways are estimated. The emergency response model (PUFF-PLUME) uses real-time data to track either instantaneous (puff) or continuous (plume) releases. A site-specific ingestion dose model was developed for use with PUFF-PLUME that includes the following ingestion dose pathways pertinent to the surrounding SRS area: milk, beef, water, and fish. The model is simplistic and can be used with existing code output.

  10. Oligodendroglial response to ionizing radiation: Dose and dose-rate response

    SciTech Connect

    Levy, R.P.

    1991-12-01

    An in vitro system using neuroglia from neonatal rat brain was developed to examine the morphologic, immunocytochemical and biochemical response of oligodendroglia to ionizing radiation. Following acute {gamma}-irradiation at day-in-culture (DIC) 8, oligodendrocyte counts at DIC 14 were 55% to 65% of control values after 2 Gy, and 29% to 36% after 5 Gy. Counts increased to near-normal levels at DIC 21 in the 2 Gy group and to 75% of normal in the 5 Gy group. Myelin basic protein levels (MBP) at DIC 14 were 60% of control values after 2 Gy, and 40% after 5 Gy. At DIC 21, MBP after 2 Gy was 45% greater than that observed at DIC 14, but MBP, as a fraction of age-matched control values, dropped from 60% to 50%. Following 5 Gy, absolute MBP changed little between DIC 14 and DIC 21, but decreased from 40% to 25% of control cultures. The response to split-dose irradiation indicated that nearly all sublethal damage in the oligodendrocyte population (and its precursors) was repaired within 3 h to 4 h. A new compartmental cell model for radiation response in vitro of the oligodendrocyte population is proposed and examined in relation to the potential reaction to radiation injury in the brain.

  11. Differential Response and Priming Dose Effect on the Proteome of Human Fibroblast and Stem Cells Induced by Exposure to Low Doses of Ionizing Radiation.

    PubMed

    Hauptmann, Monika; Haghdoost, Siamak; Gomolka, Maria; Sarioglu, Hakan; Ueffing, Marius; Dietz, Anne; Kulka, Ulrike; Unger, Kristian; Babini, Gabriele; Harms-Ringdahl, Mats; Ottolenghi, Andrea; Hornhardt, Sabine

    2016-03-01

    It has been suggested that a mechanistic understanding of the cellular responses to low dose and dose rate may be valuable in reducing some of the uncertainties involved in current risk estimates for cancer- and non-cancer-related radiation effects that are inherited in the linear no-threshold hypothesis. In this study, the effects of low-dose radiation on the proteome in both human fibroblasts and stem cells were investigated. Particular emphasis was placed on examining: 1. the dose-response relationships for the differential expression of proteins in the low-dose range (40-140 mGy) of low-linear energy transfer (LET) radiation; and 2. the effect on differential expression of proteins of a priming dose given prior to a challenge dose (adaptive response effects). These studies were performed on cultured human fibroblasts (VH10) and human adipose-derived stem cells (ADSC). The results from the VH10 cell experiments demonstrated that low-doses of low-LET radiation induced unique patterns of differentially expressed proteins for each dose investigated. In addition, a low priming radiation dose significantly changed the protein expression induced by the subsequent challenge exposure. In the ADSC the number of differentially expressed proteins was markedly less compared to VH10 cells, indicating that ADSC differ in their intrinsic response to low doses of radiation. The proteomic results are further discussed in terms of possible pathways influenced by low-dose irradiation. PMID:26934482

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

    PubMed Central

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

    2015-01-01

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

  13. 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.

  14. Analysis of bipolar linear circuit response mechanisms for high and low dose rate total dose irradiations

    SciTech Connect

    Barnaby, H.; Tausch, H.J.; Turfler, R.; Cole, P.; Baker, P.; Pease, R.L.

    1996-12-01

    A methodology is presented for the identification of circuit total dose response mechanisms in bipolar linear microcircuits irradiated at high and low dose rates. This methodology includes manual circuit analysis, circuit simulations with SPICE using extracted device parameters, and selective irradiations of portions of the circuit using a scanning electron microscope.

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

    PubMed Central

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

    1998-01-01

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

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

    PubMed

    Simpson, D G; Dallal, G E

    1989-02-01

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

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

    EPA Science Inventory

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

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

    ERIC Educational Resources Information Center

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

    2003-01-01

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

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

    EPA Science Inventory

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

  20. Updating Dosimetry for Emergency Response Dose Projections.

    PubMed

    DeCair, Sara

    2016-02-01

    In 2013, the U.S. Environmental Protection Agency (EPA) proposed an update to the 1992 Protective Action Guides (PAG) Manual. The PAG Manual provides guidance to state and local officials planning for radiological emergencies. EPA requested public comment on the proposed revisions, while making them available for interim use by officials faced with an emergency situation. Developed with interagency partners, EPA's proposal incorporates newer dosimetric methods, identifies tools and guidelines developed since the current document was issued, and extends the scope of the PAGs to all significant radiological incidents, including radiological dispersal devices or improvised nuclear devices. In order to best serve the emergency management community, scientific policy direction had to be set on how to use International Commission on Radiological Protection Publication 60 age groups in dose assessment when implementing emergency guidelines. Certain guidelines that lend themselves to different PAGs for different subpopulations are the PAGs for potassium iodide (KI), food, and water. These guidelines provide age-specific recommendations because of the radiosensitivity of the thyroid and young children with respect to ingestion and inhalation doses in particular. Taking protective actions like using KI, avoiding certain foods or using alternative sources of drinking water can be relatively simple to implement by the parents of young children. Clear public messages can convey which age groups should take which action, unlike how an evacuation or relocation order should apply to entire households or neighborhoods. New in the PAG Manual is planning guidance for the late phase of an incident, after the situation is stabilized and efforts turn toward recovery. Because the late phase can take years to complete, decision makers are faced with managing public exposures in areas not fully remediated. The proposal includes quick-reference operational guidelines to inform re-entry to

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

    PubMed Central

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

    2009-01-01

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

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

    NASA Astrophysics Data System (ADS)

    Jordan, K.; Battista, J.

    2004-01-01

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

  3. Dose- and time-response for breast cancer risk after radiation therapy for benign breast disease.

    PubMed Central

    Mattsson, A.; Rudén, B. I.; Palmgren, J.; Rutqvist, L. E.

    1995-01-01

    Exposure of the breast to ionising radiation increases the risk of breast cancer, especially among young women. However, some issues remain controversial, for instance the shape of the dose-response curve and the expression of time-related excess. The main purpose of this report was to examine the dose-response curves for radiation-induced breast cancer formulated according to radiobiological target theories. Another purpose was to analyse the time-related excess of breast cancer risk after exposure when dose and age at first exposure were held constant. Breast cancer incidence was analysed in a cohort of 3090 women diagnosed with benign breast disease during 1925-61 (median age 37 years). Of these, 1216 were treated with radiation therapy. The dose range was 0-50 Gy (mean 5.8 Gy). The incidence rate as function of dose was analysed using a linear-quadratic Poisson regression model. Cell-killing effects and other modifying effects were incorporated through additional log-linear terms. Additive and multiplicative models were compared in estimating the time-related excess. The analysis, which was based on 278 breast cancer cases, showed a linear dose-response relationship at low to medium dose levels with a cell-killing effect of 5% Gy-1 (95% confidence interval 2-9%). For a given absorbed dose and age at first exposure the time-related excess was proportional to the background rates with a suggestion that the excess remains throughout life. PMID:7547222

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

    PubMed Central

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

    2014-01-01

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

  5. Shared dosimetry error in epidemiological dose-response analyses

    DOE PAGESBeta

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

    2015-03-23

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

  6. 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.

  7. 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

  8. 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.

  9. 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

  10. Ozone-response relationships in healthy nonsmokers

    SciTech Connect

    Kulle, T.J.; Sauder, L.R.; Hebel, J.R.; Chatham, M.D.

    1985-01-01

    Significant concentration responses were observed in FVC1 FEV1, FEF 25-75, SGaw, IC, and TLC in 20 healthy, nonsmoking volunteers exposed randomly to 0.00, 0.10, 0.15, 0.20, and 0.25 ppm O3. In addition, significant response changes for FVC1 FEV1, FEF25-75 were shown with time over the 2-h exposure. Intermittent, heavy exercise (VE1 68L/min) lasting 14 min was employed every 30 min during exposure. Inspection of the concentration and time-response curves suggests that the threshold for the group response is at or below 0.15 ppm O/sub 3/. Six subjects experienced decreases > 5% in SGaw at 0.15 ppm. The concentration is only slightly higher than the 1-h O/sub 3/ National Ambient Air Quality Standard. A dose-related response was also seen for cough, nose and throat irritation, and chest discomfort. The work load, length of exposure, and individual sensitivity must be considered for establishing a safe O/sub 3/ exposure level.

  11. Ozone response relationships in healthy nonsmokers

    SciTech Connect

    Kulle, T.J.; Sauder, L.R.; Hebel, J.R.; Chatham, M.D.

    1985-07-01

    Significant concentration responses were observed in FVC, FEV1, FEF25-75, SGaw, IC, and TLC in 20 healthy, nonsmoking volunteers exposed randomly to 0.00, 0.10, 0.15, 0.20, and 0.25 ppm O/sub 3/. In addition, significant response changes for FVC, FEV1, and FEF25-75 were shown with time over the 2-h exposure. Intermittent, heavy exercise (VE, 68 L/min) lasting 14 min was employed every 30 min during exposure. Inspection of the concentration and time response curves suggests that the threshold for the group response is at or below 0.15 ppm O/sub 3/. Six subjects experienced decreases greater than 5% in FEV1 or greater than 15% in SGaw at 0.15 ppm. This concentration is only slightly higher than the 1-h O/sub 3/ National Ambient Air Quality Standard. A dose-related response was also seen for cough, nose and throat irritation, and chest discomfort. The work load, length of exposure, and individual sensitivity must be considered for establishing a safe O/sub 3/ exposure level.

  12. 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.

  13. A broadly applicable function for describing luminescence dose response

    NASA Astrophysics Data System (ADS)

    Burbidge, C. I.

    2015-07-01

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

  14. Dose-response in case-control studies.

    PubMed Central

    Berry, G

    1980-01-01

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

  15. 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).

  16. Modeling multicellular response to nonuniform distributions of radioactivity: differences in cellular response to self-dose and cross-dose.

    PubMed

    Howell, Roger W; Neti, Prasad V S V

    2005-02-01

    Radiopharmaceuticals are distributed nonuniformly in tissue. While distributions of radioactivity often appear uniform at the organ level, in fact, microscopic examination reveals that only a fraction of the cells in tissue are labeled. Labeled cells and unlabeled cells often receive different absorbed doses depending on the extent of the nonuniformity and the characteristics of the emitted radiations. The labeled cells receive an absorbed dose from radioactivity within the cell (self-dose) as well as an absorbed dose from radioactivity in surrounding labeled cells (cross-dose). Unlabeled cells receive only a cross-dose. In recent communications, a multicellular cluster model was used to investigate the lethality of microscopic nonuniform distributions of 131I iododeoxyuridine (131IdU). For a given mean absorbed dose to the tissue, the dose response depended on the percentage of cells that were labeled. Specifically, when 1, 10 and 100% of the cells were labeled, a D37 of 6.4, 5.7 and 4.5 Gy, respectively, was observed. The reason for these differences was recently traced to differences in the cellular response to the self- and cross-doses delivered by 131IdU. Systematic isolation of the effects of self-dose resulted in a D37 of 1.2 +/- 0.3 Gy. The cross-dose component yielded a D37 of 6.4 +/- 0.5 Gy. In the present work, the overall survival of multicellular clusters containing 1, 10 and 100% labeled cells is modeled using a semi-empirical approach that uses the mean lethal self- and cross-doses and the fraction of cells labeled. There is excellent agreement between the theoretical model and the experimental data when the surviving fraction is greater than 1%. Therefore, when the distribution of 131I in tissue is nonuniform at the microscopic level, and the cellular response to self- and cross-doses differs, multicellular dosimetry can be used successfully to predict biological response, whereas the mean absorbed dose fails in this regard. PMID:15658898

  17. Dose convolution filter: Incorporating spatial dose information into tissue response modeling

    SciTech Connect

    Huang Yimei; Joiner, Michael; Zhao Bo; Liao Yixiang; Burmeister, Jay

    2010-03-15

    Purpose: A model is introduced to integrate biological factors such as cell migration and bystander effects into physical dose distributions, and to incorporate spatial dose information in plan analysis and optimization. Methods: The model consists of a dose convolution filter (DCF) with single parameter {sigma}. Tissue response is calculated by an existing NTCP model with DCF-applied dose distribution as input. The authors determined {sigma} of rat spinal cord from published data. The authors also simulated the GRID technique, in which an open field is collimated into many pencil beams. Results: After applying the DCF, the NTCP model successfully fits the rat spinal cord data with a predicted value of {sigma}=2.6{+-}0.5 mm, consistent with 2 mm migration distances of remyelinating cells. Moreover, it enables the appropriate prediction of a high relative seriality for spinal cord. The model also predicts the sparing of normal tissues by the GRID technique when the size of each pencil beam becomes comparable to {sigma}. Conclusions: The DCF model incorporates spatial dose information and offers an improved way to estimate tissue response from complex radiotherapy dose distributions. It does not alter the prediction of tissue response in large homogenous fields, but successfully predicts increased tissue tolerance in small or highly nonuniform fields.

  18. 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.

  19. Clinical-dosimetric relationship between lacrimal gland dose and ocular toxicity after intensity-modulated radiotherapy for sinonasal tumours

    PubMed Central

    Batth, S S; Sreeraman, R; Dienes, E; Beckett, L A; Daly, M E; Cui, J; Mathai, M; Purdy, J A

    2013-01-01

    Objective: To characterise the relationship between lacrimal gland dose and ocular toxicity among patients treated by intensity-modulated radiotherapy (IMRT) for sinonasal tumours. Methods: 40 patients with cancers involving the nasal cavity and paranasal sinuses were treated with IMRT to a median dose of 66.0 Gy. Toxicity was scored using the Radiation Therapy Oncology Group morbidity criteria based on conjunctivitis, corneal ulceration and keratitis. The paired lacrimal glands were contoured as organs at risk, and the mean dose, maximum dose, V10, V20 and V30 were determined. Statistical analysis was performed using logistic regression and the Akaike information criterion (AIC). Results: The maximum and mean dose to the ipsilateral lacrimal gland were 19.2 Gy (range, 1.4–75.4 Gy) and 14.5 Gy (range, 11.1–67.8 Gy), respectively. The mean V10, V20 and V30 values were 50%, 25% and 17%, respectively. The incidence of acute and late Grade 3+ toxicities was 23% and 19%, respectively. Based on logistic regression and AIC, the maximum dose to the ipsilateral lacrimal gland was identified as a more significant predictor of acute toxicity (AIC, 53.89) and late toxicity (AIC, 32.94) than the mean dose (AIC, 56.13 and 33.83, respectively). The V20 was identified as the most significant predictor of late toxicity (AIC, 26.81). Conclusion: A dose–response relationship between maximum dose to the lacrimal gland and ocular toxicity was established. Our data suggesting a threshold relationship may be useful in establishing dosimetric guidelines for IMRT planning that may decrease the risk of acute and late lacrimal toxicities in the future. Advances in knowledge: A threshold relationship between radiation dose to the lacrimal gland and ocular toxicity was demonstrated, which may aid in treatment planning and reducing the morbidity of radiotherapy for sinonasal tumours. PMID:24167183

  20. 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.

  1. Methodology for Estimating Ingestion Dose for Emergency Response at SRS

    SciTech Connect

    Simpkins, A.A.

    2002-04-22

    At the Savannah River Site (SRS), emergency response models estimate dose for inhalation and ground shine pathways. A methodology has been developed to incorporate ingestion doses into the emergency response models. The methodology follows a two-phase approach. The first phase estimates site-specific derived response levels (DRLs) which can be compared with predicted ground-level concentrations to determine if intervention is needed to protect the public. This phase uses accepted methods with little deviation from recommended guidance. The second phase uses site-specific data to estimate a 'best estimate' dose to offsite individuals from ingestion of foodstuffs. While this method deviates from recommended guidance, it is technically defensibly and more realistic. As guidance is updated, these methods also will need to be updated.

  2. 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

  3. 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.

  4. [Relationship to Carcinogenesis of Repetitive Low-Dose Radiation Exposure].

    PubMed

    Ootsuyama, Akira

    2016-06-01

    We studied the carcinogenic effects caused by repetitive irradiation at a low dose, which has received attention in recent years, and examined the experimental methods used to evaluate radiation-induced carcinogenesis. For this experiment, we selected a mouse with as few autochthonous cancers as possible. Skin cancer was selected as the target for analysis, because it is a rare cancer in mice. Beta-rays were selected as the radiation source. The advantage of using beta-rays is weaker penetration power into tissues, thus protecting organs, such as the digestive and hematogenous organs. The benefit of our experimental method is that only skin cancer requires monitoring, and it is possible to perform long-term experiments. The back skin of mice was exposed repetitively to beta-rays three times a week until the occurrence of cancer or death, and the dose per exposure ranged from 0.5 to 11.8 Gy. With the high-dose range (2.5-11.8 Gy), the latency period and carcinogenic rate were almost the same in each experimental group. When the dose was reduced to 1-1.5 Gy, the latency period increased, but the carcinogenic rate remained. When the dose was further reduced to 0.5 Gy, skin cancer never happened, even though we continued irradiation until death of the last mouse in this group. The lifespan of 0.5 Gy group mice was the same as that of the controls. We showed that the 0.5 Gy dose did not cause cancer, even in mice exposed repetitively throughout their life span, and thus refer to 0.5 Gy as the threshold-like dose. PMID:27302731

  5. 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.

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

    PubMed

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

    2016-07-01

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

  7. 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

  8. Dose-Effect Relationships for the Submandibular Salivary Glands and Implications for Their Sparing by Intensity Modulated Radiotherapy

    PubMed Central

    Murdoch-Kinch, Carol-Anne; Kim, Hyugnjin M.; Vineberg, Karen A; Ship, Jonathan A.; Eisbruch, Avraham

    2012-01-01

    Purpose Submandibular salivary glands (SMGs) dysfunction contributes to xerostomia after radiotherapy (RT) of head and neck (HN) cancer. We assessed SMG dose-response relationships and their implications for sparing these glands by intensity modulated radiotherapy (IMRT). Patients and Methods 148 HN cancer patients underwent unstimulated and stimulated SMG salivary flow rate measurements selectively from Wharton’s duct orifices, before RT and periodically through 24 months after RT. Correlations of flow rates and mean SMG doses were modeled throughout all time points. IMRT re-planning in eight patients whose contralateral level I was not a target incorporated the results in a new cost function aiming to spare contralateral SMGs. Results Stimulated SMG flow rates decreased exponentially by (1.2%)Gy as mean doses increased up to 39 Gy threshold, and then plateaued near zero. At mean doses ≤39 Gy, but not higher, flow rates recovered over time at 2.2%/month. Similarly, the unstimulated salivary flow rates decreased exponentially by (3%)Gy as mean dose increased and recovered over time if mean dose was <39 Gy. IMRT re-planning reduced mean contralateral SMG dose by average 12 Gy, achieving ≤39 Gy in 5/8 patients, without target under-dosing, increasing the mean doses to the parotid glands and swallowing structures by average 2–3 Gy. Conclusions SMG salivary flow rates depended on mean dose with recovery over time up to a threshold of 39 Gy. Substantial SMG dose reduction to below this threshold and without target under-dosing is feasible in some patients, at the expense of modestly higher doses to some other organs. PMID:18337023

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

    PubMed

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

    2013-07-31

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

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

    PubMed Central

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

    2008-01-01

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

  11. DOSE-RESPONSE ASSESSMENT FOR DEVELOPMENTAL TOXICITY III. STATISTICAL MODELS

    EPA Science Inventory

    Although quantitative modeling has been central to cancer risk assessment for years, the concept of do@e-response modeling for developmental effects is relatively new. he benchmark dose (BMD) approach has been proposed for use with developmental (as well as other noncancer) endpo...

  12. PREDICTIVE BAYESIAN PATHOGEN DOSE-RESPONSE MODEL FORMS

    EPA Science Inventory

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

  13. 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 ...

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

    EPA Science Inventory

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

  15. 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.

  16. THE SHAPE OF THE TUMOR DOSE RESPONSE CURVES AT LOW PAH EXPOSURES: TESTING THE DEFAULT ASSUMPTION OF LINEARITY

    EPA Science Inventory

    We have previously characterized the administered dose tumor-response, stable DNA adduct-lung tumor response, and K-ras mutation profiles in tumors from strain A/J mice exposed i.p. to 6 PAHs including B[a]P . In summary, we demonstrated that: 1. The relationships between admini...

  17. Time and total dose response of non-volatile UVPROMs

    NASA Astrophysics Data System (ADS)

    Sampson, David F.

    1988-12-01

    The total-dose radiation response and intrinsic charge loss are reported as a function of operating time in a system. Five groups of 27C256 devices were aged from 1 to 5 years through accelerated bake to simulate system use. Characterizations of the groups with 5 years of simulated use are presented. The device margin voltage was characterized before and after aging and after exposure to five total-dose radiation levels, 1-5 krad (Si). A statistical model based upon the characterization data was developed to establish reprogramming intervals for these devices when they are used in airborne electronic systems.

  18. Dose-Effect Relationships for Individual Pelvic Floor Muscles and Anorectal Complaints After Prostate Radiotherapy

    SciTech Connect

    Smeenk, Robert Jan; Hoffmann, Aswin L.; Hopman, Wim P.M.; Lin, Emile N.J. Th. van; Kaanders, Johannes H.A.M.

    2012-06-01

    Purpose: To delineate the individual pelvic floor muscles considered to be involved in anorectal toxicity and to investigate dose-effect relationships for fecal incontinence-related complaints after prostate radiotherapy (RT). Methods and Materials: In 48 patients treated for localized prostate cancer, the internal anal sphincter (IAS) muscle, the external anal sphincter (EAS) muscle, the puborectalis muscle (PRM), and the levator ani muscles (LAM) in addition to the anal wall (Awall) and rectal wall (Rwall) were retrospectively delineated on planning computed tomography scans. Dose parameters were obtained and compared between patients with and without fecal urgency, incontinence, and frequency. Dose-effect curves were constructed. Finally, the effect of an endorectal balloon, which was applied in 28 patients, was investigated. Results: The total volume of the pelvic floor muscles together was about three times that of the Awall. The PRM was exposed to the highest RT dose, whereas the EAS received the lowest dose. Several anal and rectal dose parameters, as well as doses to all separate pelvic floor muscles, were associated with urgency, while incontinence was associated mainly with doses to the EAS and PRM. Based on the dose-effect curves, the following constraints regarding mean doses could be deduced to reduce the risk of urgency: {<=}30 Gy to the IAS; {<=}10 Gy to the EAS; {<=}50 Gy to the PRM; and {<=}40 Gy to the LAM. No dose-effect relationships for frequency were observed. Patients treated with an endorectal balloon reported significantly less urgency and incontinence, while their treatment plans showed significantly lower doses to the Awall, Rwall, and all pelvic floor muscles. Conclusions: Incontinence-related complaints show specific dose-effect relationships to individual pelvic floor muscles. Dose constraints for each muscle can be identified for RT planning. When only the Awall is delineated, substantial components of the continence apparatus are

  19. [Evaluation of the dose-effect relationship of perindopril in the treatment of arterial hypertension].

    PubMed

    Luccioni, R; Frances, Y; Gass, R; Gilgenkrantz, J M

    1989-05-01

    To evaluate the dose-effect relationship of antihypertensive drugs is essential to a rational determination of their effective dosage. Two double-blind and strictly controlled trials have demonstrated the effectiveness of perindopril 4 mg orally in the treatment of mild to moderate arterial hypertension (100 less than DAP less than 120 mmHg). The drug remained effective 24 hours after the last dose. The 2 mg dose proved insufficient to obtain a significant reduction of blood pressure. In case where the 4 mg dose was not sufficiently active, a better antihypertensive effect could be achieved with an 8 mg dose without major untoward reactions. The antihypertensive activity of perindopril was parallel to the percentage of angiotensin-converting enzyme inhibition induced by the compound. This study also illustrates clearly the value of semi-automatic blood pressure recording with the Dinamap system in the determination of dose-effect relationship, compared with the conventional sphygmomanometric method. PMID:2505712

  20. Lead in teeth from lead-dosed goats: Microdistribution and relationship to the cumulative lead dose

    SciTech Connect

    Bellis, David J.; Hetter, Katherine M.; Jones, Joseph; Amarasiriwardena, Dula; Parsons, Patrick J.

    2008-01-15

    Teeth are commonly used as a biomarker of long-term lead exposure. There appear to be few data, however, on the content or distribution of lead in teeth where data on specific lead intake (dose) are also available. This study describes the analysis of a convenience sample of teeth from animals that were dosed with lead for other purposes, i.e., a proficiency testing program for blood lead. Lead concentration of whole teeth obtained from 23 animals, as determined by atomic absorption spectrometry, varied from 0.6 to 80 {mu}g g{sup -1}. Linear regression of whole tooth lead ({mu}g g{sup -1}) on the cumulative lead dose received by the animal (g) yielded a slope of 1.2, with r{sup 2}=0.647 (p<0.0001). Laser ablation inductively coupled plasma mass spectrometry was employed to determine lead content at micrometer scale spatial resolution in the teeth of seven goats representing the dosing range. Highly localized concentrations of lead, ranging from about 10 to 2000 {mu}g g{sup -1}, were found in circumpulpal dentine. Linear regression of circumpulpal lead ({mu}g g{sup -1}) on cumulative lead dose (g) yielded a slope of 23 with r{sup 2}=0.961 (p=0.0001). The data indicated that whole tooth lead, and especially circumpulpal lead, of dosed goats increased linearly with cumulative lead exposure. These data suggest that circumpulpal dentine is a better biomarker of cumulative lead exposure than is whole tooth lead, at least for lead-dosed goats.

  1. Avertable dose intervention applied in emergency response dose evaluation system for nuclear emergency preparedness in Taiwan

    NASA Astrophysics Data System (ADS)

    Lu, Chung-hsin; Teng, Jen-hsin; Yang, Yung-muh; Chang, Bor-jing

    2010-06-01

    In Taiwan the new guides for the nuclear emergency public protective action were laid down by the Atomic Energy Council (AEC) of Executive Yuan, Taiwan, ROC on July 15th, 2005. The main modifications of the guides are that the avertable dose is applied as the intervention levels and suggests the public protective actions. The emergency response dose evaluation system named RPDOSE, which was developed in 2005, was employed in this work to enhance the capability of the avertable dose evaluation for the villages in the emergency planning zone (EPZ). The period of the long-term weather forecasting data was extended from 4 to 8 days to satisfy the requirement of avertable dose computing. According to the intervention levels, the RPDOSE system is used to calculate the avertable dose and suggest appropriate public protective actions such as sheltering, evacuation or iodine prophylaxis as well as the proposed acting times for each village in the EPZ. This system was employed and examined in the annual nuclear emergency exercise of 2008 in the Maanshan nuclear power plant.

  2. Role of heme Oxygenase-1 in low dose Radioadaptive response

    PubMed Central

    Bao, Lingzhi; Ma, Jie; Chen, Guodong; Hou, Jue; Hei, Tom K.; Yu, K.N.; Han, Wei

    2016-01-01

    Radioadaptive response (RAR) is an important phenomenon induced by low dose radiation. However, the molecular mechanism of RAR is obscure. In this study, we focused on the possible role of heme oxygenase 1 (HO-1) in RAR. Consistent with previous studies, priming dose of X-ray radiation (1–10 cGy) induced significant RAR in normal human skin fibroblasts (AG 1522 cells). Transcription and translation of HO-1 was up-regulated more than two fold by a priming dose of radiation (5 cGy). Zinc protoporphyrin Ⅸ, a specific competitive inhibitor of HO-1, efficiently inhibited RAR whereas hemin, an inducer of HO-1, could mimic priming dose of X-rays to induce RAR. Knocking down of HO-1 by transfection of HO-1 siRNA significantly attenuated RAR. Furthermore, the expression of HO-1 gene was modulated by the nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which translocated from cytoplasm to nucleus after priming dose radiation and enhance the antioxidant level of cells. PMID:26966892

  3. Role of heme Oxygenase-1 in low dose Radioadaptive response.

    PubMed

    Bao, Lingzhi; Ma, Jie; Chen, Guodong; Hou, Jue; Hei, Tom K; Yu, K N; Han, Wei

    2016-08-01

    Radioadaptive response (RAR) is an important phenomenon induced by low dose radiation. However, the molecular mechanism of RAR is obscure. In this study, we focused on the possible role of heme oxygenase 1 (HO-1) in RAR. Consistent with previous studies, priming dose of X-ray radiation (1-10cGy) induced significant RAR in normal human skin fibroblasts (AG 1522 cells). Transcription and translation of HO-1 was up-regulated more than two fold by a priming dose of radiation (5cGy). Zinc protoporphyrin Ⅸ, a specific competitive inhibitor of HO-1, efficiently inhibited RAR whereas hemin, an inducer of HO-1, could mimic priming dose of X-rays to induce RAR. Knocking down of HO-1 by transfection of HO-1 siRNA significantly attenuated RAR. Furthermore, the expression of HO-1 gene was modulated by the nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which translocated from cytoplasm to nucleus after priming dose radiation and enhance the antioxidant level of cells. PMID:26966892

  4. Dose-Effect Relationships for the Submandibular Salivary Glands and Implications for Their Sparing by Intensity Modulated Radiotherapy

    SciTech Connect

    Murdoch-Kinch, Carol-Anne; Vineberg, Karen A.; Ship, Jonathan

    2008-10-01

    Purpose: Submandibular salivary glands (SMGs) dysfunction contributes to xerostomia after radiotherapy (RT) of head-and-neck (HN) cancer. We assessed SMG dose-response relationships and their implications for sparing these glands by intensity-modulated radiotherapy (IMRT). Methods and Materials: A total of 148 HN cancer patients underwent unstimulated and stimulated SMG salivary flow rate measurements selectively from Wharton's duct orifices, before RT and periodically through 24 months after RT. Correlations of flow rates and mean SMG doses were modeled throughout all time points. IMRT replanning in 8 patients whose contralateral level I was not a target incorporated the results in a new cost function aiming to spare contralateral SMGs. Results: Stimulated SMG flow rates decreased exponentially by (1.2%){sup Gy} as mean doses increased up to 39 Gy threshold, and then plateaued near zero. At mean doses {<=}39 Gy, but not higher, flow rates recovered over time at 2.2%/month. Similarly, the unstimulated salivary flow rates decreased exponentially by (3%){sup Gy} as mean dose increased and recovered over time if mean dose was <39 Gy. IMRT replanning reduced mean contralateral SMG dose by average 12 Gy, achieving {<=}39 Gy in 5 of 8 patients, without target underdosing, increasing the mean doses to the parotid glands and swallowing structures by average 2-3 Gy. Conclusions: SMG salivary flow rates depended on mean dose with recovery over time up to a threshold of 39 Gy. Substantial SMG dose reduction to below this threshold and without target underdosing is feasible in some patients, at the expense of modestly higher doses to some other organs.

  5. BYSTANDERS, ADAPTIVE RESPONSES AND GENOMIC INSTABILITY - POTENTIAL MODIFIERS OF LOW-DOSE CANCER RESPONSES.

    EPA Science Inventory

    Bystanders, Adaptive Responses and Genomic Instability -Potential Modifiers ofLow-Dose
    Cancer Responses
    .
    There has been a concerted effort in the field of radiation biology to better understand cellular
    responses that could have an impact on the estin1ation of cancer...

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

    PubMed

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

    2015-08-21

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

  7. 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

  8. 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

  9. 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

  10. Low-Dose Gamma Radiation Does Not Induce an Adaptive Response for Micronucleus Induction in Mouse Splenocytes.

    PubMed

    Bannister, L A; Serran, M L; Mantha, R R

    2015-11-01

    Low-dose ionizing radiation is known to induce radioadaptive responses in cells in vitro as well as in mice in vivo. Low-dose radiation decreases the incidence and increases latency for spontaneous and radiation-induced tumors in mice, potentially as a result of enhanced cellular DNA repair efficiency or a reduction in genomic instability. In this study, the cytokinesis-block micronucleus (CBMN) assay was used to examine dose response and potential radioadaptive response for cytogenetic damage and cell survival in C57BL/6 and BALB/c spleen cells exposed in vitro or in vivo to low-dose 60Co gamma radiation. The effects of genetic background, radiation dose and dose rate, sampling time and cell cycle were investigated with respect to dose response and radioadaptive response. In C57BL/6 mice, a linear-quadratic dose-response relationship for the induction of micronuclei (MN) was observed for doses between 100 mGy and 2 Gy. BALB/c mice exhibited increased radiosensitivity for MN induction compared to C57BL/6 mice. A 20 mGy dose had no effect on MN frequencies in splenocytes of either mouse strain, however, increased spleen weight and a reduced number of dead cells were noted in the C57BL/6 strain only. Multiple experimental parameters were investigated in radioadaptive response studies, including dose and dose rate of the priming dose (20 mGy at 0.5 mGy/min and 100 mGy at 10 mGy/min), time interval (4 and 24 h) between priming and challenge doses, cell cycle stage (resting or proliferating) at exposure and kinetics after the challenge dose. Radioadaptive responses were not observed for MN induction for either mouse strain under any of the experimental conditions investigated. In contrast, a synergistic response for radiation-induced micronuclei in C57BL/6 spleen was detected after in vivo 20 mGy irradiation. This increase in the percentage of cells with cytogenetic damage was associated with a reduction in the number of nonviable spleen cells, suggesting that low-dose

  11. Radiation-induced genomic instability: radiation quality and dose response

    NASA Technical Reports Server (NTRS)

    Smith, Leslie E.; Nagar, Shruti; Kim, Grace J.; Morgan, William F.

    2003-01-01

    Genomic instability is a term used to describe a phenomenon that results in the accumulation of multiple changes required to convert a stable genome of a normal cell to an unstable genome characteristic of a tumor. There has been considerable recent debate concerning the importance of genomic instability in human cancer and its temporal occurrence in the carcinogenic process. Radiation is capable of inducing genomic instability in mammalian cells and instability is thought to be the driving force responsible for radiation carcinogenesis. Genomic instability is characterized by a large collection of diverse endpoints that include large-scale chromosomal rearrangements and aberrations, amplification of genetic material, aneuploidy, micronucleus formation, microsatellite instability, and gene mutation. The capacity of radiation to induce genomic instability depends to a large extent on radiation quality or linear energy transfer (LET) and dose. There appears to be a low dose threshold effect with low LET, beyond which no additional genomic instability is induced. Low doses of both high and low LET radiation are capable of inducing this phenomenon. This report reviews data concerning dose rate effects of high and low LET radiation and their capacity to induce genomic instability assayed by chromosomal aberrations, delayed lethal mutations, micronuclei and apoptosis.

  12. Cocaine cue versus cocaine dosing in humans: Evidence for distinct neurophysiological response profiles

    PubMed Central

    Reid, Malcolm S.; Flammino, Frank; Howard, Bryant; Nilsen, Diana; Prichep, Leslie S.

    2008-01-01

    Subjective, physiological and electroencephalographic (EEG) profiles were studied in cocaine dependent study participants in response to cocaine cue exposure or a dose of smoked cocaine. Both stimuli increased subjective ratings of cocaine high and craving, enhanced negative affect, and boosted plasma ACTH and skin conductance levels. However, cocaine dose produced a greater increase in high and a more prolonged increase in plasma ACTH, while cocaine cue produced a decline in skin temperature. Both stimuli produced increases in absolute theta, alpha and beta EEG power over the prefrontal cortex. However, interhemispheric EEG coherence over the prefrontal cortex decreased during cocaine cue exposure but increased following cocaine dose. Moreover, correlation analysis of subjective, physiological and EEG responding to cocaine cue and dose revealed distinct profiles. Delta and theta activity were associated with negative affect during cocaine cue exposure, but were associated with cocaine craving and reward following cocaine dosing. In both conditions, alpha activity was marker for anxiousness but not high. These data demonstrate similar subjective, physiological responding in clinical laboratory states of cocaine craving and reward. However, differences in EEG response profiles, and their relationship to function, indicate distinct neurophysiological mediators of cocaine craving and reward within the prefrontal cortex. PMID:18674556

  13. Growth rate based dose-response relationships and EC-values of ten heavy metals using the duckweed growth inhibition test (ISO 20079) with Lemna minor L. clone St.

    PubMed

    Naumann, Bianca; Eberius, Matthias; Appenroth, Klaus-J

    2007-12-01

    The duckweed Lemna minor L. clone St was used to investigate the effect of 10 heavy metals under the standardised test conditions of the ISO protocol 20079. By using growth rates derived from frond number (FN), fresh weight (FW), dry weight (DW), chlorophyll and carotenoid (Car) contents, concentration-response curves for all heavy metals and all growth parameters were classified. In addition, all data were fitted to obtain the inhibitions of growth rates (E(r)C(x)) at the level of 10%, 20% and 50% (E(r)C(10), E(r)C(20) and E(r)C(50), respectively) then used to evaluate the phytotoxicity of the different heavy metals. On the basis of the E(r)C(50) values (average ranking of all five growth parameters), the following series of phytotoxicity was detected by using molar concentrations: Ag(+)>Cd(2+)>Hg(2+)>Tl(+)>Cu(2+)>Ni(2+)>Zn(2+)>Co(2+)>Cr(VI)>As(III)>As(V). PMID:17296247

  14. AS03-Adjuvanted, Very-Low-Dose Influenza Vaccines Induce Distinctive Immune Responses Compared to Unadjuvanted High-Dose Vaccines in BALB/c Mice

    PubMed Central

    Yam, Karen K.; Gupta, Jyotsana; Winter, Kaitlin; Allen, Elizabeth; Brewer, Angela; Beaulieu, Édith; Mallett, Corey P.; Burt, David S.; Ward, Brian J.

    2015-01-01

    During the 2009–2010 influenza pandemic, an adjuvanted, dose-sparing vaccine was recommended for most Canadians. We hypothesize that differences exist in the responses to AS03-adjuvanted, low antigen (Ag) dose versus unadjuvanted, full-dose vaccines. We investigated the relationship between Ag dose and the oil-in-water emulsion Adjuvant System AS03. BALB/c mice received two IM doses of AS03A or AS03B with exaggerated dilutions of A/Uruguay/716/2007 H3N2 split virion vaccine Ag. Immune responses were assessed 3 weeks after the booster. Unadjuvanted “high” (3 μg) and low-dose (0.03–0.003 μg) vaccines generated similar serum antibody titers and cytokine secretion patterns in restimulated splenocytes. Compared to unadjuvanted “high-dose” vaccination, both AS03A and AS03B-adjuvanted low-dose vaccines tended to elicit higher serum antibody titers, broader induction of cytokine secretion and generated more influenza-specific antibody secreting cells and cytokine-secreting CD4 and CD8 T cells in splenocytes. We show that varying Ag and/or AS03 dose in this influenza vaccination mouse model can strongly influence both the magnitude and pattern of the immune response elicited. These findings are highly relevant given the likelihood of expanded use of adjuvanted, dose-sparing vaccines and raise questions about the use of “standard” doses of vaccines in pre-clinical vaccine studies. PMID:25972874

  15. Dose-and time-dependent cardiovascular responses induced by ethanol

    SciTech Connect

    Brackett, D.J.; Gauvin, D.V.; Lerner, M.R.; Lander, T.J.; Holloway, F.A.; Wilson, M.F. )

    1991-03-11

    A literature survey has revealed that a dose-response relationship between ethanol (ETOH) and serial measurements of cardiovascular parameters that include cardiac output (CO) and systemic vascular resistance (SVR) has not been established in conscious animals. The available literature in this area is controversial regarding the responses of these two parameters that control tissue blood flow. In this study, rats were instrumented for conscious cardiovascular measurements and blood sampling. Rats were monitored for 4 hrs after intragastric ETOH at 2, 4, or 6 g/kg or water. Samples for blood alcohol concentrations were taken at every measurement point and achieved peak concentrations of 63 {plus minus} 4, 103 {plus minus} 6, and 221 {plus minus} 17 mg/dl. Dose- and time-dependency were documented for decreased CO, blood pressure, respiration rate, stroke volume, and central venous pressure, and increased SVR, heart rate, and blood glucose concentrations. Thermoregulatory disturbances were observed at all doses. Blood hematocrit and lactate concentrations were unchanged. In conscious rats ethanol induced significant dose- and time-dependent hemodynamic alterations, including marked CO reduction and peripheral vasoconstriction, suggesting the potential of compromised tissue perfusion. Data also indicate that increased sympathoadrenal activity following ETOH administration may be a significant mediator of these responses. These data suggest: (1) when evaluating the physiological effects of drugs, a complete battery of cardiovascular and physiological measurements need to be assessed, and (2) when measured, these indices suggest a greater degree of compromise by ETOH than previously reported.

  16. Evaluation of the dose-effect relationship of perindopril in the treatment of hypertension.

    PubMed

    Luccioni, R; Frances, Y; Gass, R; Gilgenkrantz, J M

    1989-01-01

    The evaluation of the dose-antihypertensive effect relationship of a drug is essential for the rational determination of the effective dose. The efficacy and safety of the dose of 4 mg of perindopril in the treatment of mild-to-moderate hypertension were demonstrated by means of two double-blind studies conducted according to a rigorous methodology. This efficacy was still present 24 hours after the last dose of perindopril. The dose of 2 mg appeared to be insufficient to exert a significant antihypertensive effect. In the case of inadequate efficacy of the dose of 4 mg of perindopril, the dose of 8 mg is able to exert a greater antihypertensive effect without any major harmful effects. The antihypertensive efficacy is parallel to the percentage of converting enzyme inhibition induced by perindopril. The contribution of the automated method of blood pressure recording using the Dinamap method to establish a dose-effect relationship with reference to the classical sphygmomanometric method is clearly illustrated. PMID:2605801

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

    PubMed

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

    2010-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2014-03-01

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

  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. A normal tissue dose response model of dynamic repair processes

    NASA Astrophysics Data System (ADS)

    Alber, Markus; Belka, Claus

    2006-01-01

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

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

    EPA Science Inventory

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

  2. 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…

  3. Evaluation of the Emergency Response Dose Assessment System(ERDAS)

    NASA Technical Reports Server (NTRS)

    Evans, Randolph J.; Lambert, Winifred C.; Manobianco, John T.; Taylor, Gregory E.; Wheeler, Mark M.; Yersavich, Ann M.

    1996-01-01

    The emergency response dose assessment system (ERDAS) is a protype software and hardware system configured to produce routine mesoscale meteorological forecasts and enhanced dispersion estimates on an operational basis for the Kennedy Space Center (KSC)/Cape Canaveral Air Station (CCAS) region. ERDAS provides emergency response guidance to operations at KSC/CCAS in the case of an accidental hazardous material release or an aborted vehicle launch. This report describes the evaluation of ERDAS including: evaluation of sea breeze predictions, comparison of launch plume location and concentration predictions, case study of a toxic release, evaluation of model sensitivity to varying input parameters, evaluation of the user interface, assessment of ERDA's operational capabilities, and a comparison of ERDAS models to the ocean breeze dry gultch diffusion model.

  4. Dose—response relationships for agents inhibiting the immune response

    PubMed Central

    Berenbaum, M. C.; Brown, I. N.

    1964-01-01

    Mice were injected with T.A.B. vaccine and, 2 days later, with various doses of different compounds. The relation between dose of compound, mortality and antibody production was studied, and therapeutic indices were calculated for a number of compounds. The most effective agent in suppressing antibody production at relatively non-toxic doses was cyclophosphamide, with next amethopterin (the effect of which was, however, inexplicably erratic), 6-thioguanine and 6-mercaptopurine, in that order. Vincaleukoblastine, triethylene melamine, triethylenethiophosphoramide, mannomustine and 5-fluorouracil were less effective. Compounds of a miscellaneous group (boric acid, caffeine, sodium nitrite, bacitracin, neomycin and polymyxin `B') were studied in the same way: they had no effect on antibody production, even in lethal doses. PMID:14113077

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

    PubMed

    Kratzer, D D; Littell, R C

    2006-05-01

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

  6. The Dose Response Relationship in Psychotherapy: Implications for Social Policy

    ERIC Educational Resources Information Center

    Harnett, Paul; O'Donovan, Analise; Lambert, Michael J.

    2010-01-01

    The principle aim of this study was to estimate the number of sessions of psychotherapy needed for clients suffering from psychiatric illness to return to a normal state of functioning or reliably improve. This would be helpful for treatment planning and policy decisions regarding how much therapy is enough. The progress of 125 clients entering…

  7. 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

  8. 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...

  9. OZONE RESPONSE RELATIONSHIPS IN HEALTHY NONSMOKERS

    EPA Science Inventory

    Significant concentration responses were observed in FVC1 FEV1, FEF 25-75, SGaw, IC, and TLC in 20 healthy, nonsmoking volunteers exposed randomly to 0.00, 0.10, 0.15, 0.20, and 0.25 ppm O3. In addition, significant response changes for FVC1 FEV1, FEF25-75 were shown with time ov...

  10. 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

  11. Dose-dependent changes in the locomotor responses to methamphetamine in BALB/c mice: Low doses induce hypolocomotion

    PubMed Central

    Singh, Rana A. K.; Kosten, Therese A.; Kinsey, Berma M.; Shen, Xiaoyun; Lopez, Angel Y.; Kosten, Thomas R.; Orson, Frank M.

    2012-01-01

    The overall goal of the present study was to determine the effects of different doses of (+)-methamphetamine (meth) on locomotor activity of Balb/C mice. Four experiments were designed to test a wide range of meth doses in BALB/c female mice. In Experiment 1, we examined locomotor activity induced by an acute administration of low doses of meth (0.01 and 0.03 mg/kg) in a 90-min session. Experiment 2 was conducted to test higher meth doses (0.3 – 10 mg/kg). In Experiment 3, separate sets of mice were pre-treated with various meth doses once or twice (one injection/week) prior to a locomotor challenge with a low meth dose. Finally, in Experiment 4, we tested whether locomotor activation would be affected by pretreatment with a low or moderate dose of meth one month prior to the low meth dose challenge. Results show that low doses of meth induce hypolocomotion whereas moderate to high doses induce hyperlocomotion. Prior exposure to either one moderate or high dose of meth or to two, low doses of meth attenuated the hypolocomotor effect of a low meth dose one week later. This effect was also attenuated in mice tested one month after administration of a moderate meth dose. These results show that low and high doses of meth can have opposing effects on locomotor activity. Further, prior exposure to the drug leads to tolerance, rather than sensitization, of the hypolocomotor response to low meth doses. PMID:23010423

  12. Clozapine-Related EEG Changes and Seizures: Dose and Plasma-Level Relationships

    PubMed Central

    Varma, Seema; Bishara, Delia; Besag, Frank M. C.; Taylor, David

    2011-01-01

    Clozapine is a widely used atypical antipsychotic with a unique effectiveness in treatment-resistant schizophrenia. An important adverse effect is seizures, which have been observed at all stages of clozapine treatment. Valproate has traditionally been considered the drug of choice for the prophylaxis of clozapine seizures, however it may not be the most suitable choice for all patients. There is disagreement as to the best point to prescribe valproate or a suitable antiepileptic: as seizure prophylaxis at a certain clozapine dose or level, or only as remedial treatment. In this review, we examine the relevant literature with an aim to evaluate the following relationships: clozapine dose and electroencephalogram (EEG) abnormalities, plasma levels and EEG abnormalities, dose and occurrence of seizures and plasma levels and occurrence of seizures. Weighted linear regression models were fitted to investigate these relationships. There was a strong relationship between clozapine dose and plasma level and occurrence of clozapine-induced EEG abnormalities. However, a statistically significant relationship between dose and occurrence of seizures was not found. A relationship between clozapine plasma level and occurrence of seizures was not established because of the scarcity of useful data although our review found three case reports which suggested that there is a very substantial risk of seizures with clozapine plasma levels exceeding 1300 μg/l. Seizures are more common during the initiation phase of clozapine treatment, suggesting a slow titration to target plasma levels is desirable. An antiepileptic drug should be considered when the clozapine plasma level exceeds 500 μg/l, if the EEG shows clear epileptiform discharges, if seizures, myoclonic jerks or speech difficulties occur and when there is concurrent use of epileptogenic medication. The antiepileptics of choice for the treatment and prophylaxis of clozapine-induced seizures are valproate (particularly where

  13. Mutans Streptococci Dose Response to Xylitol Chewing Gum

    PubMed Central

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

    2008-01-01

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

  14. Biological bases for cancer dose-response extrapolation procedures

    SciTech Connect

    Wilson, J.D. )

    1991-01-01

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

  15. Enhancement of phototropic response to a range of light doses in Triticum aestivum coleoptiles in clinostat-simulated microgravity

    NASA Technical Reports Server (NTRS)

    Heathcote, D. G.; Bircher, B. W.; Brown, A. H. (Principal Investigator)

    1987-01-01

    The phototropic dose-response relationship has been determined for Triticum aestivum cv. Broom coleoptiles growing on a purpose-built clinostat apparatus providing gravity compensation by rotation about a horizontal axis at 2 rev min-1. These data are compared with data sets obtained with the clinostat axis vertical and stationary, as a 1 g control, and rotating vertically to examine clinostat effects other than gravity compensation. Triticum at 1 g follows the well-established pattern of other cereal coleoptiles with a first positive curvature at low doses, followed by an indifferent response region, and a second positive response at progressively increasing doses. However, these response regions lie at higher dose levels than reported for Avena. There is no significant difference between the responses observed with the clinostat axis vertical in the rotating and stationary modes, but gravity compensation by horizontal rotation increases the magnitude of first and second positive curvatures some threefold at 100 min after stimulation. The indifferent response is replaced by a significant curvature towards the light source, but remains apparent as a reduced curvature response at these dose levels.

  16. The role of mindfulness in romantic relationship satisfaction and responses to relationship stress.

    PubMed

    Barnes, Sean; Brown, Kirk Warren; Krusemark, Elizabeth; Campbell, W Keith; Rogge, Ronald D

    2007-10-01

    Two studies examined the role of mindfulness in romantic relationship satisfaction and in responses to relationship stress. Using a longitudinal design, Study 1 found that higher trait mindfulness predicted higher relationship satisfaction and greater capacities to respond constructively to relationship stress. Study 2 replicated and extended these findings. Mindfulness was again shown to relate to relationship satisfaction; then, using a conflict discussion paradigm, trait mindfulness was found to predict lower emotional stress responses and positive pre- and postconflict change in perception of the relationship. State mindfulness was related to better communication quality during the discussion. Both studies indicated that mindfulness may play an influential role in romantic relationship well-being. Discussion highlights future research directions for this new area of inquiry. PMID:17935531

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

    PubMed Central

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

    2013-01-01

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

  18. Defining the Optimal Selenium Dose for Prostate Cancer Risk Reduction: Insights from the U-Shaped Relationship Between Selenium Status, DNA Damage, and Apoptosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Our work in dogs has revealed a U-shaped dose response between selenium status and prostatic DNA damage that remarkably parallels the relationship between dietary selenium and prostate cancer risk in men, suggesting that more selenium is not necessarily better. Herein, we extend this canine work to ...

  19. Critical target and dose and dose-rate responses for the induction of chromosomal instability by ionizing radiation

    NASA Technical Reports Server (NTRS)

    Limoli, C. L.; Corcoran, J. J.; Milligan, J. R.; Ward, J. F.; Morgan, W. F.

    1999-01-01

    To investigate the critical target, dose response and dose-rate response for the induction of chromosomal instability by ionizing radiation, bromodeoxyuridine (BrdU)-substituted and unsubstituted GM10115 cells were exposed to a range of doses (0.1-10 Gy) and different dose rates (0.092-17.45 Gy min(-1)). The status of chromosomal stability was determined by fluorescence in situ hybridization approximately 20 generations after irradiation in clonal populations derived from single progenitor cells surviving acute exposure. Overall, nearly 700 individual clones representing over 140,000 metaphases were analyzed. In cells unsubstituted with BrdU, a dose response was found, where the probability of observing delayed chromosomal instability in any given clone was 3% per gray of X rays. For cells substituted with 25-66% BrdU, however, a dose response was observed only at low doses (<1.0 Gy); at higher doses (>1.0 Gy), the incidence of chromosomal instability leveled off. There was an increase in the frequency and complexity of chromosomal instability per unit dose compared to cells unsubstituted with BrdU. The frequency of chromosomal instability appeared to saturate around approximately 30%, an effect which occurred at much lower doses in the presence of BrdU. Changing the gamma-ray dose rate by a factor of 190 (0.092 to 17.45 Gy min(-1)) produced no significant differences in the frequency of chromosomal instability. The enhancement of chromosomal instability promoted by the presence of the BrdU argues that DNA comprises at least one of the critical targets important for the induction of this end point of genomic instability.

  20. The relationship between infecting dose and severity of disease in reported outbreaks of Salmonella infections.

    PubMed Central

    Glynn, J. R.; Bradley, D. J.

    1992-01-01

    The relationship between size of the infecting dose and severity of the resulting disease has been investigated for salmonella infections by reanalysis of data within epidemics for 32 outbreaks, and comparing data between outbreaks for 68 typhoid epidemics and 49 food-poisoning outbreaks due to salmonellas. Attack rate, incubation period, amount of infected food consumed and type of vehicle are used as proxy measures of infecting dose, while case fatality rates for typhoid and case hospitalization rates for food poisoning salmonellas were used to assess severity. Limitations of the data are discussed. Both unweighted and logit analysis models are used. There is no evidence for a dose-severity relationship for Salmonella typhi, but evidence of a correlation between dose and severity is available from within-epidemic or between-epidemic analysis, or both, for Salmonella typhimurium, S. enteritidis, S. infantis, S. newport, and S. thompson. The presence of such a relationship affects the way in which control interventions should be assessed. PMID:1468522

  1. 40 CFR 109.4 - Relationship to Federal response actions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 21 2010-07-01 2010-07-01 false Relationship to Federal response actions. 109.4 Section 109.4 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS CRITERIA FOR STATE, LOCAL AND REGIONAL OIL REMOVAL CONTINGENCY PLANS § 109.4 Relationship...

  2. 40 CFR 109.4 - Relationship to Federal response actions.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 23 2012-07-01 2012-07-01 false Relationship to Federal response actions. 109.4 Section 109.4 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS CRITERIA FOR STATE, LOCAL AND REGIONAL OIL REMOVAL CONTINGENCY PLANS § 109.4 Relationship...

  3. 40 CFR 109.4 - Relationship to Federal response actions.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 22 2014-07-01 2013-07-01 true Relationship to Federal response actions. 109.4 Section 109.4 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS CRITERIA FOR STATE, LOCAL AND REGIONAL OIL REMOVAL CONTINGENCY PLANS § 109.4 Relationship...

  4. 40 CFR 109.4 - Relationship to Federal response actions.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 23 2013-07-01 2013-07-01 false Relationship to Federal response actions. 109.4 Section 109.4 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS CRITERIA FOR STATE, LOCAL AND REGIONAL OIL REMOVAL CONTINGENCY PLANS § 109.4 Relationship...

  5. 40 CFR 109.4 - Relationship to Federal response actions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 22 2011-07-01 2011-07-01 false Relationship to Federal response actions. 109.4 Section 109.4 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS CRITERIA FOR STATE, LOCAL AND REGIONAL OIL REMOVAL CONTINGENCY PLANS § 109.4 Relationship...

  6. Fewer doses of HPV vaccine result in immune response similar to three-dose regimen

    Cancer.gov

    NCI scientists report that two doses of a human papillomavirus (HPV) vaccine, trademarked as Cervarix, resulted in similar serum antibody levels against two of the most carcinogenic types of HPV (16 and 18), compared to a standard three dose regimen.

  7. Drug and light dose responses to focal photodynamic therapy of single blood vessels in vivo

    NASA Astrophysics Data System (ADS)

    Khurana, Mamta; Moriyama, Eduardo H.; Mariampillai, Adrian; Samkoe, Kimberley; Cramb, David; Wilson, Brian C.

    2009-11-01

    As part of an ongoing program to develop two-photon (2-γ) photodynamic therapy (PDT) for treatment of wet-form age-related macular degeneration (AMD) and other vascular pathologies, we have evaluated the reciprocity of drug-light doses in focal-PDT. We targeted individual arteries in a murine window chamber model, using primarily the clinical photosensitizer Visudyne/liposomal-verteporfin. Shortly after administration of the photosensitizer, a small region including an arteriole was selected and irradiated with varying light doses. Targeted and nearby vessels were observed for a maximum of 17 to 25 h to assess vascular shutdown, tapering, and dye leakage/occlusion. For a given end-point metric, there was reciprocity between the drug and light doses, i.e., the response correlated with the drug-light product (DLP). These results provide the first quantification of photosensitizer and light dose relationships for localized irradiation of a single blood vessel and are compared to the DLP required for vessel closure between 1-γ and 2-γ activation, between focal and broad-beam irradiation, and between verteporfin and a porphyrin dimer with high 2-γ cross section. Demonstration of reciprocity over a wide range of DLP is important for further development of focal PDT treatments, such as the targeting of feeder vessels in 2-γ PDT of AMD.

  8. 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.

  9. 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.

  10. 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

  11. 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).

  12. 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

  13. The dose-effect relationships between torture and psychiatric symptoms in Vietnamese ex-political detainees and a comparison group.

    PubMed

    Mollica, R F; McInnes, K; Pham, T; Smith Fawzi, M C; Murphy, E; Lin, L

    1998-09-01

    The purpose of this study was to determine in Vietnamese ex-political detainees newly arrived into the United States a) the prevalence of torture and psychiatric symptoms and b) the dose-effect relationships between cumulative torture experience and the psychiatric symptoms of posttraumatic stress disorder (PTSD) and major depression. The study population included Vietnamese ex-political detainees (N = 51) and a comparison group (N = 22). All respondents received culturally validated instruments with known psychometric properties including Vietnamese versions of the Hopkins Symptom Checklist-25 and the Harvard Trauma Questionnaire. The ex-political detainees, in contrast to the comparison group, had experienced more torture events (12.2 SD = 4.2 vs. 2.6 SD = 3.1) and had higher rates of PTSD (90% vs. 79%) and depression (49% vs. 15%). Dose-effect relationships between cumulative torture experience and psychiatric symptoms were positive with the PTSD subcategory of "increased arousal" revealing the strongest association. These findings provide evidence that torture is associated with psychiatric morbidity in Vietnamese refugees. The demonstration of significant dose-effect responses supports the hypothesis that torture is a major risk factor in the etiology of major depression and PTSD. The generalizability of these results to other torture survivor groups is unknown. The interaction between torture and other pre- and post-migration risk factors over time in different cultural settings still needs to be examined. PMID:9741560

  14. Notes on the effect of dose uncertainty

    SciTech Connect

    Morris, M.D.

    1987-01-01

    The apparent dose-response relationship between amount of exposure to acute radiation and level of mortality in humans is affected by uncertainties in the dose values. It is apparent that one of the greatest concerns regarding the human data from Hiroshima and Nagasaki is the unexpectedly shallow slope of the dose response curve. This may be partially explained by uncertainty in the dose estimates. Some potential effects of dose uncertainty on the apparent dose-response relationship are demonstrated.

  15. Radiation myelopathy in the rat: an interpretation of dose effect relationships

    SciTech Connect

    Leith, J.T.; DeWyngaert, J.K.; Glicksman, A.S.

    1981-12-01

    Data were collected on the production of overt paralysis in the rat after low linear energy transfer (LET) ionizing radiation exposure of different regions of the spinal cord. Data from both single and multiple radiation exposure schedules were interpreted using the ED/sub 50/ value (estimated dose needed to produce 50% paralysis in a group of irradiated animals) as the isoeffect comparison dose. Plots were made of the reciprocal of the ED/sub 50/ total dose versus the size of the dose per fraction used. The use of multifractionation data in such a way allows implications to be made about the nature of the in vivo response curve. These reciprocal dose plots indicate that the spinal cord normal tissue system shows two responses that may be specifically characterized by the ratio of the intercept (..cap alpha..) of the linear regression fit of the reciprocal total dose versus dose per fraction curve to the slope (..beta..) of the curve (..cap alpha../..beta..). For rat spinal cord, this value is about 3.8 +/- 0.4 (standard error) for the thoraco-lumbar region and about 2.0 +/- 0.3 (standard error) for the cervical region. While absolute dose response data vary somewhat among investigators, all of the data on production of paralysis in rats show similar trends with respect to the (..cap alpha../..beta..) ratio. We feel this ratio may uniquely characterize this (and other) normal tissue systems. Knowledge of this parameter and how it varies after different treatments (e.g., high LET radiation exposure) may be important.

  16. Radiation myelopathy in the rat: an interpretation of dose effect relationships

    SciTech Connect

    Leith, J.T.; DeWyngaert, J.K.; Glicksman, A.S.

    1981-12-01

    Data were collected on the production of overt paralysis in the rat after low linear energy transfer (LET) ionizing radiation exposure of different regions of the spinal cord. Data from both single and multiple radiation exposure schedules were interpreted using the ED/sub 50/ value (estimated dose needed to produce 50% paralysis in a group of irradiated animals) as the isoeffect comparison dose. Plots were made of the reciprocal of the ED/sub 50/ total dose versus the size of the dose per fraction used. The use of multifractionation data in such a way allows implications to be made about the nature of the in vivo response curve. These reciprocal dose plots indicate that the spinal cord normal tissue system shows two responses that may be specifically characterized by the ration of the intercept (..cap alpha..) of the linear regression fit of the reciprocal total dose versus dose per fraction curve to the slope (..beta..) of the curve (..cap alpha../..beta..). For rat spinal cord, this value is about 3.8 +/- 0.4 (standard error) for the thoraco-lumbar region and about 2.0 +/- 0.3 (standard error) for the cervical region. While absolute dose response data vary somewhat among investigators, all of the data on production of paralysis in rats show similar trends with respect the the (..cap alpha../..beta..) ratio. We feel that this ratio may uniquely characterize this (and other) normal tissue systems. Knowledge of this parameter and how it varies after different treatments (e.g., high LET radiation exposure) may be important.

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

    PubMed

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

    2016-06-10

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

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

    EPA Science Inventory

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

  19. Cellular response of the rat brain to single doses of 137Cs γ rays does not predict its response to prolonged ‘biologically equivalent’ fractionated doses

    PubMed Central

    Greene-Schloesser, Dana M.; Kooshki, Mitra; Payne, Valerie; D’Agostino, Ralph B.; Wheeler, Kenneth T.; Metheny-Barlow, Linda J.; Robbins, Mike E.

    2014-01-01

    Purpose To determine if the brain’s response to single doses predicts its response to ‘biologically equivalent’ fractionated doses. Methods Young adult male Fischer 344 rats were whole-brain irradiated with either single 11, 14, or 16.5 Gy doses of 137Cs γ rays or their ‘biologically equivalent’ 20, 30, or 40 Gy fractionated doses (fWBI) delivered in 5 Gy fractions, twice/week for 2, 3, or 4 weeks, respectively. At 2 months post-irradiation, cellular markers of inflammation (total, activated, and newborn microglia) and neurogenesis (newborn neurons) were measured in 40 µm sections of the dentate gyrus (DG). Results Although the total number of microglia in the DG/hilus was not significantly different (p > 0.7) in unirradiated, single dose, and fWBI rats, single doses produced a significant (p < 0.003) increase in the percent-activated microglia; fWBI did not (p > 0.1). Additionally, single doses produced a significant (p < 0.002) dose-dependent increase in surviving newborn microglia; fWBI did not (p < 0.8). Although total proliferation in the DG was reduced equally by single and fWBI doses, single doses produced a significant dose-dependent (p < 0.02) decrease in surviving newborn neurons; fWBI did not (p > 0.6). Conclusions These data demonstrate that the rat brain’s cellular response to single doses often does not predict its cellular response to ‘biologically equivalent’ fWBI doses. PMID:24937374

  20. Risk and responsibility: a complex and evolving relationship.

    PubMed

    Kermisch, Céline

    2012-03-01

    This paper analyses the nature of the relationship between risk and responsibility. Since neither the concept of risk nor the concept of responsibility has an unequivocal definition, it is obvious that there is no single interpretation of their relationship. After introducing the different meanings of responsibility used in this paper, we analyse four conceptions of risk. This allows us to make their link with responsibility explicit and to determine if a shift in the connection between risk and responsibility can be outlined. (1) In the engineer's paradigm, the quantitative conception of risk does not include any concept of responsibility. Their relationship is indirect, the locus of responsibility being risk management. (2) In Mary Douglas' cultural theory, risks are constructed through the responsibilities they engage. (3) Rayner and (4) Wolff go further by integrating forms of responsibility in the definition of risk itself. Analysis of these four frameworks shows that the concepts of risk and responsibility are increasingly intertwined. This tendency is reinforced by increasing public awareness and a call for the integration of a moral dimension in risk management. Therefore, we suggest that a form of virtue-responsibility should also be integrated in the concept of risk. PMID:21103951

  1. SU-F-18C-12: On the Relationship of the Weighted Dose to the Surface Dose In Abdominal CT - Patient Size Dependency

    SciTech Connect

    Zhou, Y; Scott, A; Allahverdian, J

    2014-06-15

    Purpose: It is possible to measure the patient surface dose non-invasively using radiolucent dosimeters. However, the patient size specific weighted dose remains unknown. We attempted to study the weighted dose to surface dose relationship as the patient size varies in abdominal CT. Methods: Seven abdomen phantoms (CIRS TE series) simulating patients from an infant to a large adult were used. Size specific doses were measured with a 100 mm CT chamber under axial scans using a Siemens Sensation 64 (mCT) and a GE 750 HD. The scanner settings were 120 kVp, 200 mAs with fully opened collimations. Additional kVps (80, 100, 140) were added depending on the phantom sizes. The ratios (r) of the weighted CT dose (Dw) to the surface dose (Ds) were related to the phantom size (L) defined as the diameter resulting the equivalent cross-sectional area. Results: The Dw versus Ds ratio (r) was fitted to a linear relationship: r = 1.083 − 0.007L (R square = 0.995), and r = 1.064 − 0.007L (R square = 0.953), for Siemens Sensation 64 and GE 750 HD, respectively. The relationship appears to be independent of the scanner specifics. Conclusion: The surface dose to the weighted dose ratio decreases linearly as the patient size increases. The result is independent of the scanner specifics. The result can be used to obtain in vivo CT dosimetry in abdominal CT.

  2. Dose calculation and in-phantom measurement in BNCT using response matrix method.

    PubMed

    Rahmani, Faezeh; Shahriari, Majid

    2011-12-01

    In-phantom measurement of physical dose distribution is very important for Boron Neutron Capture Therapy (BNCT) planning validation. If any changes take place in therapeutic neutron beam due to the beam shaping assembly (BSA) change, the dose will be changed so another group of simulations should be carried out for dose calculation. To avoid this time consuming procedure and speed up the dose calculation to help patients not wait for a long time, response matrix method was used. This procedure was performed for neutron beam of the optimized BSA as a reference beam. These calculations were carried out using the MCNPX, Monte Carlo code. The calculated beam parameters were measured for a SNYDER head phantom placed 10 cm away from beam the exit of the BSA. The head phantom can be assumed as a linear system and neutron beam and dose distribution can be assumed as an input and a response of this system (head phantom), respectively. Neutron spectrum energy was digitized into 27 groups. Dose response of each group was calculated. Summation of these dose responses is equal to a total dose of the whole neutron/gamma spectrum. Response matrix is the double dimension matrix (energy/dose) in which each parameter represents a depth-dose resulted from specific energy. If the spectrum is changed, response of each energy group may be differed. By considering response matrix and energy vector, dose response can be calculated. This method was tested for some BSA, and calculations show statistical errors less than 10%. PMID:21450471

  3. Risk Factors and Dose-Effect Relationship for Mandibular Osteoradionecrosis in Oral and Oropharyngeal Cancer Patients

    SciTech Connect

    Lee, Ik Jae; Koom, Woong Sub; Lee, Chang Geol; Kim, Yong Bae; Yoo, Sei Whan; Keum, Ki Chang; Kim, Gwi Eon; Choi, Eun Chang; Cha, In Ho

    2009-11-15

    Purpose: To analyze risk factors and the dose-effect relationship for osteoradionecrosis (ORN) of the mandible after radiotherapy of oral and oropharyngeal cancers. Materials and Methods: One-hundred ninety-eight patients with oral (45%) and oropharyngeal cancer (55%) who had received external radiotherapy between 1990 and 2000 were retrospectively reviewed. All patients had a dental evaluation before radiotherapy. The median radiation dose was 60 Gy (range, 16-75 Gy), and the median biologically effective dose for late effects (BED{sub late}) in bone was 114 Gy{sub 2} (range, 30-167 Gy{sub 2}). Results: The frequency of ORN was 13 patients (6.6%). Among patients with mandibular surgery, eight had ORN at the surgical site. Among patients without mandibular surgery, five patients had ORN on the molar area of the mandible. The median time to ORN was 22 months (range, 1-69 months). Univariate analysis revealed that mandibular surgery and Co-60 were significant risk factors for ORN (p = 0.01 and 0.04, respectively). In multivariate analysis, mandibular surgery was the most important factor (p = 0.001). High radiation doses over BED 102.6 Gy{sub 2} (conventional dose of 54 Gy at 1.8 Gy/fraction) were also a significant factor for ORN (p = 0.008) and showed a positive dose-effect relationship in logistic regression (p = 0.04) for patients who had undergone mandibular surgery. Conclusions: Mandibular surgery was the most significant risk factor for ORN of mandible in oral and oropharyngeal cancers patients. A BED of 102.6 Gy{sub 2} or higher to the mandible also significantly increases the risk of ORN.

  4. Relationship between clozapine dose, serum concentration, and clinical outcome in children and adolescents in clinical practice.

    PubMed

    Wohkittel, Christopher; Gerlach, Manfred; Taurines, Regina; Wewetzer, Christoph; Unterecker, Stefan; Burger, Rainer; Schreck, Diana; Mehler-Wex, Claudia; Romanos, Marcel; Egberts, Karin

    2016-08-01

    Information on dose- and concentration-related clinical effects of clozapine treatment in children and adolescents is scarce. This study aimed to examine the relationship between dose, serum concentration, and clinical outcome as well as the influencing factors thereof in paediatric patients treated with clozapine. Data from a routine Therapeutic Drug Monitoring (TDM) service between 2004 and 2014 were studied in 68 patients, aged 11-18 years. Severity of illness, therapeutic effectiveness and adverse drug reactions (ADRs) were assessed by standardized means. A relationship between the daily dose (mean 319 mg, 4.9 mg/kg) and serum concentration (mean 387 ng/ml) of clozapine was found with the variation in dose explaining 30 % of the variability in clozapine serum concentrations. Also gender contributed to the variability, however, no influence of age or concomitant medications was detected. Furthermore, a significant association was found between clozapine serum concentration and the occurrence of ADRs. Patients without ADRs had a lower mean serum concentration than those with mild (261.4 vs 407.3 ng/ml, P = 0.018) and moderate ADRs (261.4 vs 416.3 ng/ml, P = 0.028). As clozapine was estimated to be effective in lower blood concentrations, guidance on a possibly lower therapeutic range of clozapine serum levels in paediatric patients is provided. With ADRs increasing under higher concentrations, TDM is strongly recommended in paediatric clozapine therapy for individualized dosing. Dose adjustment in females also might be reasonable according to gender-related differences in serum concentrations. However, regarding the limitations of this study results should be validated in larger studies with more standardized designs. PMID:27221285

  5. Fibrinolytic response in women on low-dose oral contraceptive.

    PubMed

    Ishak, R; Ahmad, R; Gudum, H R; Hassan, K; Ang, E S

    1992-06-01

    Long term use of low doses of combination oral contraceptives appears to increase plasminogen level, thereby increasing fibrinolytic activity and reducing the risk of thromboembolism. Blood levels of plasminogen, tissue plasminogen activator (tPA), and plasminogen activator inhibitor (PAI), were measured before and after stress (5 minutes of stair climbing) in a group of 30 women, 23-40 years old, who had taken 30 mcg of ethinyl estradiol with 150 mcg of desogestrel or levonorgestrel for at least 1 year. Similar measurements were taken from a control group of 30 women matched for age, height, and weight. Plasminogen and tPA levels in both groups increased significantly after exercise. The level of PAI did not change significantly with stress in either group. The level of plasminogen was significantly higher in the group taking contraceptives, whether before or after exercise, when compared to the control group. Levels of tPA and PAI, although slightly increased in the oral contraceptive group, were not significantly different between the two groups. The increase in plasminogen may be due to the estrogen component of the contraceptives. Stress seems to increase fibrinolytic response. PMID:12345026

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

    NASA Technical Reports Server (NTRS)

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

    1972-01-01

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

  7. 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.

  8. High-Dose Atomoxetine Treatment of ADHD in Youths with Limited Response to Standard Doses

    ERIC Educational Resources Information Center

    Kratochvil, Christopher J.; Michelson, David; Newcorn, Jeffrey H.; Weiss, Margaret D.; Busner, Joan; Moore, Rodney J.; Ruff, Dustin D.; Ramsey, Janet; Dickson, Ruth; Turgay, Atilla; Saylor, Keith E.; Luber, Stephen; Vaughan, Brigette; Allen, Albert J.

    2007-01-01

    Objective: To assess the utility and tolerability of higher than standard atomoxetine doses to treat attention-deficit/hyperactivity disorder (ADHD). Method: Two randomized, double-blind trials of atomoxetine nonresponders ages 6 to 16 years were conducted comparing continued treatment with same-dose atomoxetine to treatment using greater than…

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

    PubMed

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

    2003-02-01

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

  10. Estradiol valerate and alcohol intake: dose-response assessments

    PubMed Central

    Quirarte, Gina L; Reid, Larry D; de la Teja, I Sofía Ledesma; Reid, Meta L; Sánchez, Marco A; Díaz-Trujillo, Arnulfo; Aguilar-Vazquez, Azucena; Prado-Alcalá, Roberto A

    2007-01-01

    Background An injection of estradiol valerate (EV) provides estradiol for a prolonged period. Recent research indicates that a single 2.0 mg injection of EV modifies a female rat's appetite for alcoholic beverages. This research extends the initial research by assessing 8 doses of EV (from .001 to 2.0 mg/female rat), as well assessing the effects of 2.0 mg EV in females with ovariectomies. Results With the administration of EV, there was a dose-related loss of bodyweight reaching the maximum loss, when it occurred, at about 4 days after injections. Subsequently, rats returned to gaining weight regularly. Of the doses tested, only the 2.0 mg dose produced a consistent increase in intake of ethanol during the time previous research indicated that the rats would show enhanced intakes. There was, however, a dose-related trend for smaller doses to enhance intakes. Rats with ovariectomies showed a similar pattern of effects, to intact rats, with the 2 mg dose. After extensive histories of intake of alcohol, both placebo and EV-treated females had estradiol levels below the average measured in females without a history of alcohol-intake. Conclusion The data support the conclusion that pharmacological doses of estradiol can produce enduring changes that are manifest as an enhanced appetite for alcoholic beverages. The effect can occur among females without ovaries. PMID:17335585

  11. 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.

  12. Dose response characteristics of special opti-chromic waveguides

    NASA Astrophysics Data System (ADS)

    Humprerys, K. C.; Kantz, A. D.

    In 1981 Kronenberg, McLaughlin, and Siebentritt proposed measurement of radiation dosage using optical waveguides with leuco dye solutions. Based on this work, an opti-chromic system was proposed at the Fourth International Meeting on Radiation Processing. This opti-chromic system has been evaluated by McLaughlin and Radak. The opti-chromic waveguide system may be even more valuable for other applications which involve measurements with special requirements and configurations. The linearity of the radiation response can be enhanced by proper selection of leuco dye concentration, waveguide materials, organic activator solvents, and trace chemical additives. This paper presents experimental data resulting from an examination of the organic solvents TEP, DMSO, and n-propyl alcohol in relationship to stability, temperature characteristics, and radiation chemistry. The experimental data indicates that by varying the types and combinations of organic solvents, special opti-chromic waveguides can be fabricated to measure various radiation ranges under a variety of temperature ranges which have stability over time.

  13. On the relationship of minimum detectable contrast to dose and lesion size in abdominal CT.

    PubMed

    Zhou, Yifang; Scott, Alexander; Allahverdian, Janet; Lee, Christina; Kightlinger, Blake; Azizyan, Avetis; Miller, Joseph

    2015-10-01

    CT dose optimization is typically guided by pixel noise or contrast-to-noise ratio that does not delineate low contrast details adequately. We utilized the statistically defined low contrast detectability to study its relationship to dose and lesion size in abdominal CT. A realistically shaped medium sized abdomen phantom was customized to contain a cylindrical void of 4 cm diameter. The void was filled with a low contrast (1% and 2%) insert containing six groups of cylindrical targets ranging from 1.2 mm to 7 mm in size. Helical CT scans were performed using a Siemens 64-slice mCT and a GE Discovery 750 HD at various doses. After the subtractions between adjacent slices, the uniform sections of the filtered backprojection reconstructed images were partitioned to matrices of square elements matching the sizes of the targets. It was verified that the mean values from all the elements in each matrix follow a Gaussian distribution. The minimum detectable contrast (MDC), quantified by the mean signal to background difference equal to the distribution's standard deviation multiplied by 3.29, corresponding to 95% confidence level, was found to be related to the phantom specific dose and the element size by a power law (R^2  >  0.990). Independent readings on the 5 mm and 7 mm targets were compared to the measured contrast to the MDC ratios. The results showed that 93% of the cases were detectable when the measured contrast exceeds the MDC. The correlation of the MDC to the pixel noise and target size was also identified and the relationship was found to be the same for the scanners in the study. To quantify the impact of iterative reconstructions to the low contrast detectability, the noise structure was studied in a similar manner at different doses and with different ASIR blending fractions. The relationship of the dose to the blending fraction and low contrast detectability is presented. PMID:26389637

  14. On the relationship of minimum detectable contrast to dose and lesion size in abdominal CT

    NASA Astrophysics Data System (ADS)

    Zhou, Yifang; Scott, Alexander, II; Allahverdian, Janet; Lee, Christina; Kightlinger, Blake; Azizyan, Avetis; Miller, Joseph

    2015-10-01

    CT dose optimization is typically guided by pixel noise or contrast-to-noise ratio that does not delineate low contrast details adequately. We utilized the statistically defined low contrast detectability to study its relationship to dose and lesion size in abdominal CT. A realistically shaped medium sized abdomen phantom was customized to contain a cylindrical void of 4 cm diameter. The void was filled with a low contrast (1% and 2%) insert containing six groups of cylindrical targets ranging from 1.2 mm to 7 mm in size. Helical CT scans were performed using a Siemens 64-slice mCT and a GE Discovery 750 HD at various doses. After the subtractions between adjacent slices, the uniform sections of the filtered backprojection reconstructed images were partitioned to matrices of square elements matching the sizes of the targets. It was verified that the mean values from all the elements in each matrix follow a Gaussian distribution. The minimum detectable contrast (MDC), quantified by the mean signal to background difference equal to the distribution’s standard deviation multiplied by 3.29, corresponding to 95% confidence level, was found to be related to the phantom specific dose and the element size by a power law (R^2  >  0.990). Independent readings on the 5 mm and 7 mm targets were compared to the measured contrast to the MDC ratios. The results showed that 93% of the cases were detectable when the measured contrast exceeds the MDC. The correlation of the MDC to the pixel noise and target size was also identified and the relationship was found to be the same for the scanners in the study. To quantify the impact of iterative reconstructions to the low contrast detectability, the noise structure was studied in a similar manner at different doses and with different ASIR blending fractions. The relationship of the dose to the blending fraction and low contrast detectability is presented.

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

    PubMed

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

    2016-05-01

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

  16. 3'-deoxy-3'-[{sup 18}F]fluorothymidine PET Quantification of Bone Marrow Response to Radiation Dose

    SciTech Connect

    McGuire, Sarah M.; Menda, Yusuf; Boles Ponto, Laura L.; Gross, Brandie; Buatti, John; Bayouth, John E.

    2011-11-01

    Purpose: The purpose of this study was to quantify the relationship of bone marrow response to radiation dose, using 3'-deoxy-3'-[{sup 18}F]fluorothymidine ([{sup 18}F]FLT)-labeled uptake quantified in positron-emission tomography (PET) scans. Methods and Materials: Pre- and post-Week 1 treatment [{sup 18}F]FLT PET images were registered to the CT images used to create the radiation treatment plan. Changes in [{sup 18}F]FLT uptake values were measured using profile data of standardized uptake values (SUVs) and doses along the vertebral bodies located at a field border where a range of radiation doses were present for 10 patients. Data from the profile measurements were grouped into 1 Gy dose bins from 1 to 9 Gy to compare SUV changes for all patients. Additionally, the maximum pretreatment, the post-Week 1 treatment, and the dose values located within the C6-T7 vertebrae that straddled the field edge were measured for all patients. Results: Both the profile and the individual vertebral data showed a strong correlation between SUV change and radiation dose. Relative differences in SUVs between bins >1 Gy and <7 Gy were statistically significant (p < 0.01, two-sample t test). The reduction in SUV was approximately linear until it reached a reduction threshold of 75%-80% in SUV for doses greater than 6 Gy/week for both the dose-binned data and the vertebral maximum SUVs. Conclusions: The change in SUV observed in head and neck cancer patients treated with chemoradiation shows the potential for using [{sup 18}F]FLT PET images for identifying active bone marrow and monitoring changes due to radiation dose. Additionally, the change in [{sup 18}F]FLT uptake observed in bone marrow for different weekly doses suggests potential dose thresholds for reducing bone marrow toxicity.

  17. The relationship between carbohydrate and the mealtime insulin dose in type 1 diabetes.

    PubMed

    Bell, Kirstine J; King, Bruce R; Shafat, Amir; Smart, Carmel E

    2015-01-01

    A primary focus of the nutritional management of type 1 diabetes has been on matching prandial insulin therapy with carbohydrate amount consumed. Different methods exist to quantify carbohydrate including counting in one gram increments, 10g portions or 15g exchanges. Clinicians have assumed that counting in one gram increments is necessary to precisely dose insulin and optimize postprandial control. Carbohydrate estimations in portions or exchanges have been thought of as inadequate because they may result in less precise matching of insulin dose to carbohydrate amount. However, studies examining the impact of errors in carbohydrate quantification on postprandial glycemia challenge this commonly held view. In addition it has been found that a single mealtime bolus of insulin can cover a range of carbohydrate intake without deterioration in postprandial control. Furthermore, limitations exist in the accuracy of the nutrition information panel on a food label. This article reviews the relationship between carbohydrate quantity and insulin dose, highlighting limitations in the evidence for a linear association. These insights have significant implications for patient education and mealtime insulin dose calculations. PMID:26422396

  18. Relationship between response rates and measures of reinforcing strength using a choice procedure in monkeys.

    PubMed

    Banks, Matthew L; Gould, Robert W; Czoty, Paul W; Nader, Michael A

    2008-07-01

    Concurrent schedules of reinforcement are increasingly being used to investigate the reinforcing strength of abused drugs. A purported advantage of concurrent schedules is that the primary dependent measure, percentage of responses emitted on the drug-associated manipulandum, is independent of the rate-altering effects of drugs. Data supporting this hypothesis are, however, rarely presented, which was one goal of this study. In addition, we tested the hypothesis that drug-induced decreases in response rates provides an additional index to characterize abuse liability of drugs. This study examined the relationship between response rate and response allocation (i.e. drug choice) when 3,4-methylenedioxymethamphetamine (MDMA, 0.03-0.3 mg/kg/inj) or cocaine (0.003-0.1 mg/kg/inj) was the alternative to food under concurrent fixed-ratio reinforcement schedules in rhesus (n=4) and cynomolgus (n=16) monkeys, respectively. Increasing doses of MDMA or cocaine resulted in increased drug choice and dose-dependent decreases in overall response rates. For both drugs, response rates on the drug-associated lever were not affected by dose and were not different from saline. Furthermore, at most doses, rates of responding on the food-associated lever were significantly higher than response rates on the drug-associated lever. Finally, MDMA but not cocaine decreased food-reinforced responding, providing evidence for potential differences between the drugs. These results demonstrate that under concurrent food-drug reinforcement schedules, response rates on the drug-associated lever are independent of measures of reinforcement, whereas disruptions in food-maintained responding may be inversely related to abuse liability. PMID:18622187

  19. Slipped femoral capital epiphyses in irradiated children: dose, volume and age relationships

    SciTech Connect

    Silverman, C.L.; Thomas, P.R.M.; McAlister, W.H.; Walker, S.; Whiteside, L.A.

    1981-10-01

    Between 1960 and 1979, 50 patients under 15 years of age received radiotherapy to the pelvis including the non-fused capital femoral epiphyseal plate. A total of 83 epiphyseal plates were at risk. Eight epiphyseal plates (9.6%) in five patients were abnormal: symptomatic capital femoral epiphyseal slippage--4, asymptomatic slippage--1, severe epiphyseal abnormalities of radiographs--3. No complication occurred below doses of 2,500 rad (25 Gy). Children under the age of 4 at time of irradiation were at a higher risk (7/15-47%) than those over 4 years of age (1/21-4.7%). Most slippages occurred at ages between 8 and 10 years. No dose response curve was obtained--higher doses above the threshold dose of 2,500 rad did not increase the incidence of slippage. A mechanism of action is postulated. This is a preventable complication; judicious use of primary or secondary blocking systems can eliminate or limit the dose to the non-fused epiphyseal plate and prevent later morbid complications.

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

    PubMed

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

    2015-07-29

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

  1. Temperature dependence of ethanol depression in mice: dose response.

    PubMed

    Finn, D A; Syapin, P J; Bejanian, M; Jones, B L; Alkana, R L

    1994-04-01

    Manipulation of body temperature during intoxication significantly alters brain sensitivity to ethanol. The current study tested the generality of this effect within the hypnotic dose range. Drug naive, male C57BL/6J mice were injected with 3.2, 3.6, or 4.0 g/kg ethanol (20% w/v) and were exposed to 1 of 7 designated temperatures from 13 degrees to 34 degrees C to manipulate body temperature during intoxication. Rectal temperature at return of righting reflex (RORR) was significantly, positively correlated with loss of righting reflex (LORR) duration and significantly, negatively correlated with blood ethanol concentration (BEC) at RORR at all three doses. These results indicate that increasing body temperature during intoxication increased ethanol sensitivity in C57 mice at all three doses tested and demonstrate the generality of temperature dependence across hypnotic doses in these animals. Interestingly, the LORR duration was dose-dependent at each ambient temperature, but the degree of body temperature change and the BEC at RORR were not dose-dependent. Overall, these results emphasize the importance of body temperature as a variable in ethanol research. PMID:8048742

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

    NASA Astrophysics Data System (ADS)

    Jordan, K.; Battista, J.

    2004-01-01

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

  3. 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.

  4. 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.

  5. High dose medroxyprogesterone acetate (MPA) treatment in metastatic carcinoma of the breast: a dose-response evaluation.

    PubMed

    Cuna, G R; Calciati, A; Strada, M R; Bumma, C; Campio, L

    1978-04-30

    The results of controlled clinical trial that used high doses of medroxyprogesterone acetate (MPA) in the treatment of metastatic breast cancer are reported. Two treatment reigmens were used: regimen A, 500 mg daily with a total dose of 30 g; regimen B, 1,000 mg daily with a total dose of 60 g. The overall response rates were similar, with no statistically significant difference between the two treated groups. Regimen A (lower dosage group) reached a remission rate of 44%, whereas regimen B (higher dosage group) had a remission rate of 41%. The mean duration of response was 8 months with regimen A and 9 months with regimen B. The advantages of the lower dosage regimen as opposed to the higher dosage regimen of MPA in the treatment of advanced breast cancer are discussed. PMID:354147

  6. 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...

  7. 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...

  8. 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...

  9. Molecular dissection of the roles of the SOD genes in mammalian response to low dose irradiation

    SciTech Connect

    Li, Chuan-Yaun

    2009-01-27

    “Molecular dissection of the roles of the SOD genes in mammalian response to low dose irradiation " was started on 09/01/03 and ended on 08/31/07. The primary objective of the project was to carry out mechanistic studies of the roles of the anti-oxidant SOD genes in mammalian cellular response to low dose ionizing radiation.

  10. 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...

  11. Relationship between grain crop yield potential and nitrogen response

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cereal grain fertilizer nitrogen (N) recommendations should conform to accepted theory. The objective of this study was to evaluate the relationship between yield potential (yield level) and N responsiveness in long-term winter wheat (Triticum aestivum L.) and maize (Zea mays L.) field experiments ...

  12. The Relationship between Awareness and Attention: Evidence from ERP Responses

    ERIC Educational Resources Information Center

    Koivisto, Mika; Kainulainen, Pasi; Revonsuo, Antti

    2009-01-01

    The relationship between attention and awareness is complex, because both concepts can be understood in different ways. Here we review our recent series of experiments which have tracked the independent contributions of different types of visual attention and awareness to electrophysiological brain responses, and then we report a new experiment…

  13. 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

  14. Graded-threshold parametric response maps: towards a strategy for adaptive dose painting

    NASA Astrophysics Data System (ADS)

    Lausch, A.; Jensen, N.; Chen, J.; Lee, T. Y.; Lock, M.; Wong, E.

    2014-03-01

    Purpose: To modify the single-threshold parametric response map (ST-PRM) method for predicting treatment outcomes in order to facilitate its use for guidance of adaptive dose painting in intensity-modulated radiotherapy. Methods: Multiple graded thresholds were used to extend the ST-PRM method (Nat. Med. 2009;15(5):572-576) such that the full functional change distribution within tumours could be represented with respect to multiple confidence interval estimates for functional changes in similar healthy tissue. The ST-PRM and graded-threshold PRM (GT-PRM) methods were applied to functional imaging scans of 5 patients treated for hepatocellular carcinoma. Pre and post-radiotherapy arterial blood flow maps (ABF) were generated from CT-perfusion scans of each patient. ABF maps were rigidly registered based on aligning tumour centres of mass. ST-PRM and GT-PRM analyses were then performed on overlapping tumour regions within the registered ABF maps. Main findings: The ST-PRMs contained many disconnected clusters of voxels classified as having a significant change in function. While this may be useful to predict treatment response, it may pose challenges for identifying boost volumes or for informing dose-painting by numbers strategies. The GT-PRMs included all of the same information as ST-PRMs but also visualized the full tumour functional change distribution. Heterogeneous clusters in the ST-PRMs often became more connected in the GT-PRMs by voxels with similar functional changes. Conclusions: GT-PRMs provided additional information which helped to visualize relationships between significant functional changes identified by ST-PRMs. This may enhance ST-PRM utility for guiding adaptive dose painting.

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

    PubMed

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

    2015-12-01

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

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

    PubMed Central

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

    2015-01-01

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

  17. DOSE-RESPONSE MODELING FOR ASSESSING CUMULATIVE PESTICIDE RISK

    EPA Science Inventory

    This project is still in its early phases. Future work in this area will involve theoretical analyses of the limits of dose-additivity assumptions, and physiologically-based pharmacokinetic and pharmacodynamic (PBPK/PD) models for n-methyl carbamate and pyrethroid pesticides (in ...

  18. BIOLOGICALLY BASED DOSE RESPONSE MODELS FOR DEVELOPMENTAL TOXICITY RISK ASSESSMENT

    EPA Science Inventory

    Present risk assessment procedures for non-cancer endpoints generally rely on the determination of No Observed Adverse Effects Levels (NOAELS) in animal models followed by the application of various Uncertainty Factors (UFs) to account for unknowns in extrapolating high dose toxi...

  19. 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.

  20. Dose response to chlorthalidone in patients with mild hypertension. Efficacy of a lower dose.

    PubMed

    Materson, B J; Oster, J R; Michael, U F; Bolton, S M; Burton, Z C; Stambaugh, J E; Morledge, J

    1978-08-01

    A multicenter study of chlorthalidone was performed to determine the relative antihypertensive efficacy and side effects of doses lower than those usually recommended for therapy. After a 4-wk placebo control period 100 patients with mild hypertension were randomly assigned doubleblind to 12.5-, 25-, 50-, or 75-mg regimens of chlorthalidone or to placebo for 12 wk. The groups of patients taking 25, 50, and 75 mg had declines in blood pressure which were not significantly different from each other. Serum potassium decreased in the 50- and 75-mg groups but not significantly in the 25-mg group. We conclude that chlorthalidone, 25 mg daily, was at least as effective for hypertension as 50 and 75 mg with less perturbation of potassium. Use of smaller initial diuretic doses may provide equal efficacy with fewer side effects for many patients. PMID:354839

  1. Improved tumour response prediction with equivalent uniform dose in pre-clinical study using direct intratumoural infusion of liposome-encapsulated 186Re radionuclides

    NASA Astrophysics Data System (ADS)

    Hrycushko, Brian A.; Ware, Steve; Li, Shihong; Bao, Ande

    2011-09-01

    Crucial to all cancer therapy modalities is a strong correlation between treatment and effect. Predictability of therapy success/failure allows for the optimization of treatment protocol and aids in the decision of whether additional treatment is necessary to prevent tumour progression. This work evaluated the relationship between cancer treatment and effect for intratumoural infusions of liposome-encapsulated 186Re to head and neck squamous cell carcinoma xenografts of nude rats. Absorbed dose calculations using a dose-point kernel convolution technique showed significant intratumoural dose heterogeneity due to the short range of the beta-particle emissions. The use of three separate tumour infusion locations improved dose homogeneity compared to a single infusion location as a result of a more uniform radioactivity distribution. An improved dose-response correlation was obtained when using effective uniform dose (EUD) calculations based on a generic set of radiobiological parameters (R2 = 0.84) than when using average tumour absorbed dose (R2 = 0.22). Varying radiobiological parameter values over ranges commonly used for all types of tumours showed little effect on EUD calculations, which suggests that individualized parameter use is of little significance as long as the intratumoural dose heterogeneity is taken into consideration in the dose-response relationship. The improved predictability achieved when using EUD calculations for this cancer therapy modality may be useful for treatment planning and evaluation.

  2. A Review: Development of a Microdose Model for Analysis of Adaptive Response and Bystander Dose Response Behavior

    PubMed Central

    Leonard, Bobby E.

    2008-01-01

    Prior work has provided incremental phases to a microdosimetry modeling program to describe the dose response behavior of the radio-protective adaptive response effect. We have here consolidated these prior works (Leonard 2000, 2005, 2007a, 2007b, 2007c) to provide a composite, comprehensive Microdose Model that is also herein modified to include the bystander effect. The nomenclature for the model is also standardized for the benefit of the experimental cellular radio-biologist. It extends the prior work to explicitly encompass separately the analysis of experimental data that is 1.) only dose dependent and reflecting only adaptive response radio-protection, 2.) both dose and dose-rate dependent data and reflecting only adaptive response radio-protection for spontaneous and challenge dose damage, 3.) only dose dependent data and reflecting both bystander deleterious damage and adaptive response radio-protection (AR-BE model). The Appendix cites the various applications of the model. Here we have used the Microdose Model to analyze the, much more human risk significant, Elmore et al (2006) data for the dose and dose rate influence on the adaptive response radio-protective behavior of HeLa x Skin cells for naturally occurring, spontaneous chromosome damage from a Brachytherapy type 125I photon radiation source. We have also applied the AR-BE Microdose Model to the Chromosome inversion data of Hooker et al (2004) reflecting both low LET bystander and adaptive response effects. The micro-beam facility data of Miller et al (1999), Nagasawa and Little (1999) and Zhou et al (2003) is also examined. For the Zhou et al (2003) data, we use the AR-BE model to estimate the threshold for adaptive response reduction of the bystander effect. The mammogram and diagnostic X-ray induction of AR and protective BE are observed. We show that bystander damage is reduced in the similar manner as spontaneous and challenge dose damage as shown by the Azzam et al (1996) data. We cite

  3. The Inhibitory Effects of Low-Dose Ionizing Radiation in IgE-Mediated Allergic Responses

    PubMed Central

    Nam, Seon Young; Yang, Kwang Hee; Kim, Cha Soon; Lee, In Kyung; Kim, Ji Young

    2015-01-01

    Ionizing radiation has different biological effects according to dose and dose rate. In particular, the biological effect of low-dose radiation is unclear. Low-dose whole-body gamma irradiation activates immune responses in several ways. However, the effects and mechanism of low-dose radiation on allergic responses remain poorly understood. Previously, we reported that low-dose ionizing radiation inhibits mediator release in IgE-mediated RBL-2H3 mast cell activation. In this study, to have any physiological relevance, we investigated whether low-dose radiation inhibits allergic responses in activated human mast cells (HMC-1(5C6) and LAD2 cells), mouse models of passive cutaneous anaphylaxis and the late-phase cutaneous response. High-dose radiation induced cell death, but low-dose ionizing radiation of <0.5 Gy did not induce mast cell death. Low-dose ionizing radiation that did not induce cell death significantly suppressed mediator release from human mast cells (HMC-1(5C6) and LAD2 cells) that were activated by antigen-antibody reaction. To determine the inhibitory mechanism of mediator released by low-dose ionizing radiation, we examined the phosphorylation of intracellular signaling molecules such as Lyn, Syk, phospholipase Cγ, and protein kinase C, as well as the intracellular free Ca2+ concentration ([Ca2+]i). The phosphorylation of signaling molecules and [Ca2+]i following stimulation of FcεRI receptors was inhibited by low dose ionizing radiation. In agreement with its in vitro effect, ionizing radiation also significantly inhibited inflammatory cells infiltration, cytokine mRNA expression (TNF-α, IL-4, IL-13), and symptoms of passive cutaneous anaphylaxis reaction and the late-phase cutaneous response in anti-dinitrophenyl IgE-sensitized mice. These results indicate that ionizing radiation inhibits both mast cell-mediated immediate- and delayed-type allergic reactions in vivo and in vitro. PMID:26317642

  4. The Inhibitory Effects of Low-Dose Ionizing Radiation in IgE-Mediated Allergic Responses.

    PubMed

    Joo, Hae Mi; Kang, Su Jin; Nam, Seon Young; Yang, Kwang Hee; Kim, Cha Soon; Lee, In Kyung; Kim, Ji Young

    2015-01-01

    Ionizing radiation has different biological effects according to dose and dose rate. In particular, the biological effect of low-dose radiation is unclear. Low-dose whole-body gamma irradiation activates immune responses in several ways. However, the effects and mechanism of low-dose radiation on allergic responses remain poorly understood. Previously, we reported that low-dose ionizing radiation inhibits mediator release in IgE-mediated RBL-2H3 mast cell activation. In this study, to have any physiological relevance, we investigated whether low-dose radiation inhibits allergic responses in activated human mast cells (HMC-1(5C6) and LAD2 cells), mouse models of passive cutaneous anaphylaxis and the late-phase cutaneous response. High-dose radiation induced cell death, but low-dose ionizing radiation of <0.5 Gy did not induce mast cell death. Low-dose ionizing radiation that did not induce cell death significantly suppressed mediator release from human mast cells (HMC-1(5C6) and LAD2 cells) that were activated by antigen-antibody reaction. To determine the inhibitory mechanism of mediator released by low-dose ionizing radiation, we examined the phosphorylation of intracellular signaling molecules such as Lyn, Syk, phospholipase Cγ, and protein kinase C, as well as the intracellular free Ca2+ concentration ([Ca2+]i). The phosphorylation of signaling molecules and [Ca2+]i following stimulation of FcεRI receptors was inhibited by low dose ionizing radiation. In agreement with its in vitro effect, ionizing radiation also significantly inhibited inflammatory cells infiltration, cytokine mRNA expression (TNF-α, IL-4, IL-13), and symptoms of passive cutaneous anaphylaxis reaction and the late-phase cutaneous response in anti-dinitrophenyl IgE-sensitized mice. These results indicate that ionizing radiation inhibits both mast cell-mediated immediate- and delayed-type allergic reactions in vivo and in vitro. PMID:26317642

  5. Dose-effect relationships of nucleoplasmic bridges and complex nuclear anomalies in human peripheral lymphocytes exposed to 60Co γ-rays at a relatively low dose.

    PubMed

    Tian, Xue-Lei; Zhao, Hua; Cai, Tian-Jing; Lu, Xue; Chen, De-Qing; Li, Shuang; Liu, Qing-Jie

    2016-07-01

    The dose effect between nucleoplasmic bridges (NPB) and relatively low doses of ionising radiation remains unknown. Accordingly, this study investigated the NPB frequencies in human peripheral blood lymphocytes exposed to low-dose (60)Co γ-rays. Complex anomalies, including fused nuclei (FUS), horse-shoe nuclei (HS) and circular nuclei (CIR), which possibly originated from multiple NPBs, were also scored. Human peripheral blood samples were collected from three healthy males and irradiated with 0-1 and 0-0.4 Gy (60)Co γ-rays. A cytokinesis-block micronucleus cytome assay was then conducted to analyse NPB, PFHC (NPB plus three complex nuclear anomalies) and micronucleus (MN) in binucleated cells. All dose-response curves followed the linear model for both NPB frequency and PFHC cell frequency. The dose-response curves between NPB frequency and absorbed dose at 0-1 and 0-0.4 Gy were y = 0.0037x + 0.0005 (R (2) = 0.979, P < 0.05) and y = 0.0043x + 0.0004 (R (2) = 0.941, P < 0.05), respectively. The dose-response curves between PFHC cell frequency and absorbed dose at 0-1 and 0-0.4 Gy were y = 0.0044x + 0.0007 (R (2) = 0.982, P < 0.05) and y = 0.0059x + 0.0005 (R (2) = 0.969, P < 0.05), respectively. The statistical significance of differences between the irradiated groups (0-0.4 Gy) and background levels of NPB, PFHC and MN were also analysed. The lowest analysable doses of NPB, PFHC and MN were 0.12, 0.08 and 0.08 Gy, respectively. In conclusion, NPBs and PFHC positively correlated with the absorbed radiation at a relatively low dose. PMID:26833100

  6. Testing the relationship between the solar radiation dose and surface DMS concentrations using in situ data

    NASA Astrophysics Data System (ADS)

    Miles, C. J.; Bell, T. G.; Lenton, T. M.

    2009-09-01

    The proposed strong positive relationship between dimethylsulphide (DMS) concentration and the solar radiation dose (SRD) received into the surface ocean is tested using data from the Atlantic Meridional Transect (AMT) programme. In situ, daily data sampled concurrently with DMS concentrations is used for the component variables of the SRD (mixed layer depth, MLD, surface insolation, I0, and a light attenuation coefficient, k) to calculate SRDinsitu. This is the first time in situ data for all of the components, including k, has been used to test the SRD-DMS relationship over large spatial scales. We find a significant correlation (ρ=0.55 n=65 p<0.01) but the slope of this relationship (0.006 nM/W m-2) is less than previously found at the global (0.019 nM/W m-2) and regional scales (Blanes Bay, Mediterranean, 0.028 nM/W m-2; Sargasso Sea 0.017 nM/W m-2). The correlation is improved (ρ=0.74 n=65 p<0.01) by replacing the in situ data with an estimated I0 (which assumes a constant 50% removal of the top of atmosphere value; 0.5×TOA), a MLD climatology and a fixed value for k following previous work. Equally strong, but non-linear relationships are also found between DMS and both in situ MLD (ρ=0.61 n=65 p<0.01) and the estimated I0 (ρ=0.73 n=65 p<0.01) alone. Using a satellite-retrieved, cloud-adjusted surface UVA irradiance to calculate a UV radiation dose (UVRD) with a climatological MLD also provides an equivalent correlation (ρ=0.67 n=54 p<0.01) to DMS. With this data, MLD appears the dominant control upon DMS concentrations and remains a useful shorthand to prediction without fully resolving the biological processes involved. However, the implied relationship between the incident solar/ultraviolet radiation (modulated by MLD), and sea surface DMS concentrations, is critical for closing a climate feedback loop.

  7. Human Lymphocytes Response to Low Gamma-ray Doses

    NASA Astrophysics Data System (ADS)

    Vega-Carrillo, Héctor René; Manzanares-Acuña, Eduardo; Bañuelos-Valenzuela, Rómulo

    2002-08-01

    Radiation and non-radiation workers lymphocytes were exposed to a low strength gamma-ray field to determine heat shock protein expression in function of radiation dose. Protein identification was carried out using mAb raised against Hsp25, Hsp60, Hsp70 and Hsp90; from these, only Hsp70 protein was detected before and after lymphocyte irradiation. In all cases, an increasing trend of relative amounts of Hsp70 in function to irradiation time was observed. After 70.5 uGy gamma-ray dose, radiation worker's lymphocytes expressed more Hsp70 protein, than non radiation workers' lymphocytes, indicating a larger tolerance to gamma rays (gammatolerance), due to an adaptation process developed by his labor condition.

  8. Responses of astrocytes in culture after low dose laser irradiation

    SciTech Connect

    Yew, D.T.; Zheng, D.R.; Au, C.; Li, W.W. )

    1990-03-01

    The effect of Helium-Neon low dose laser on astrocytes was investigated in cultures of isolated astrocytes from albino neonatal rats. The laser appeared to inhibit the growth of astrocytes as exemplified by the smaller sizes of the cells and the decreased leucine uptake in each cell after treatment. Temporary decrease in the number of mitoses was also observed, but this trend was reversed soon after. Electron microscopic studies revealed an increase in buddings from cell bodies and processes (branches) after irradiation.

  9. External beam radiotherapy for palliation of painful bone metastases: pooled data bioeffect dose response analysis of dose fractionation

    NASA Astrophysics Data System (ADS)

    Naveen, T.; Supe, Sanjay S.; Ganesh, K. M.; Samuel, Jacob

    2009-01-01

    Bone metastases develop in up to 70% of newly diagnosed cancer patients and result in immobility, anxiety, and depression, severely diminishing the patients quality of life. Radiotherapy is a frequently used modality for bone metastasis and has been shown to be effective in reducing metastatic bone pain and in some instances, causing tumor shrinkage or growth inhibition. There is controversy surrounding the optimal fractionation schedule and total dose of external beam radiotherapy, despite many randomized trials and overviews addressing the issue. This study was undertaken to apply BED to clinical fractionation data of radiotherapeutic management of bone metastases in order to arrive at optimum BED values for acceptable level of response rate. A computerised literature search was conducted to identify all prospective clinical studies that addressed the issue of fractionation for the treatment of bone metastasis. The results of these studies were pooled together to form the database for the analysis. A total of 4111 number of patients received radiation dose ranging from 4 to 40.5 Gy in 1 to 15 fractions with dose per fraction ranging from 2 to 10 Gy. Single fraction treatments were delivered in 2013 patients and the dose varied from 4 to 10 Gy. Multifraction treatments were delivered in 2098 patients and the dose varied from 15 to 40.5 Gy. The biological effective dose (BED) was evaluated for each fractionation schedule using the linear quadratic model and an α/β value of 10 Gy. Response rate increased significantly beyond a BED value of 14.4 Gy (p < 0.01). Based on our analysis and indications from the literature about higher retreatment and fracture rate of single fraction treatments, minimum BED value of 14.4 Gy is recommended.

  10. 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

  11. Low Dose Studies with Focused X-Rays in cell and Tissue Models: Mechanisms of Bystander and Genomic Instability Responses

    SciTech Connect

    Kathy Held; Kevin Prise; Barry Michael; Melvyn Folkard

    2002-12-14

    the relationship between high- and low-dose exposures. The targeting approach also allows us to study very clearly a newly recognized effect of radiation, the ''bystander effect'', which appears to dominate some low-dose responses and therefore may have a significant role in low-dose risk mechanisms. Our project also addresses the concept that the background of naturally occurring oxidative damage that takes place continually in cells due to byproducts of metabolism may play a role in low-dose radiation risk. This project therefore also examines how cells are damaged by treatments that modify the levels of oxidative damage, either alone or in combination with low-dose irradiation. In this project, we have used human and rodent cell lines and each set of experiments has been carried out on a single cell type. However, low-dose research has to extend into tissues because signaling between cells of different types is likely to influence the responses. Our studies have therefore also included microbeam experiments using a model tissue system that consists of an explant of a small piece of pig ureter grown in culture. The structure of this tissue is similar to that of epithelium and therefore it relates to the tissues in which carcinoma arises. Our studies have been able to measure bystander-induced changes in the cells growing out from the tissue fragment after it has been targeted with a few radiation tracks to mimic a low-dose exposure.

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

    PubMed

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

    2005-06-01

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

  13. 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

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

    PubMed

    Brown, Denver M Y; Bray, Steven R

    2015-01-01

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

  15. Sublinear response in lacZ mutant frequency of Muta™ Mouse spermatogonial stem cells after low dose subchronic exposure to N-ethyl-N-nitrosourea.

    PubMed

    O'Brien, Jason M; Walker, Mike; Sivathayalan, Ahalya; Douglas, George R; Yauk, Carole L; Marchetti, Francesco

    2015-05-01

    The transgenic rodent mutation assay was used to compare the dose-response relationship of lacZ mutant frequency (MF) in spermatogonial stem cells exposed acutely or subchronically to N-ethyl-N-nitrosourea (ENU). Muta(™) Mouse males were exposed orally to 0, 25, 50, or 100 mg/kg ENU for acute exposures and 0, 1, 2, or 5 mg/(kg day) for 28-day subchronic exposures. LacZ MF was measured in sperm collected 70 days post-exposure to target spermatogonial stem cells. Dose-response data were fit to linear, quadratic, exponential, or power models. Acute exposure resulted in a dose-dependent increase in MF that was significant (P < 0.05) at all doses tested and was best described by a quadratic dose-response model that was linear in the low dose range. In contrast, similar total doses fragmented over a 28-day subchronic exposure only resulted in a significant increase in lacZ MF at the highest dose tested. Therefore, the subchronic no observable genotoxic effect level (NOGEL) was 2 mg/(kg day) (or 56 mg/kg total dose). The subchronic dose-response was best described by the exponential and power models, which were sublinear in the low dose range. Benchmark dose lower confidence limits (BMDLs) for acute and subchronic exposure were 3.0 and 1.0 mg/(kg day) (or 27.4 mg/kg total dose), respectively. These findings are supportive of a saturable DNA repair mechanism as the mutagenic mode of action for ENU in spermatogonia and imply that sufficiently low exposures would not cause appreciable genotoxic effects over background. This may have important implications for the quantitative risk assessment of germ cell mutagens. PMID:25598316

  16. Parotid Glands Dose-Effect Relationships Based on Their Actually Delivered Doses: Implications for Adaptive Re-Planning in Radiotherapy of Head and Neck Cancer

    PubMed Central

    Hunter, Klaudia U.; Fernandes, Laura; Vineberg, Karen A.; McShan, Daniel; Antonuk, Alan E.; Cornwall, Craig; Feng, Mary; Schipper, Mathew; Balter, James; Eisbruch, Avraham

    2013-01-01

    Purpose Doses actually delivered to the parotid glands during radiotherapy often exceed planned doses. We hypothesized that the delivered doses correlate better with parotid salivary output than the planned doses, used in all previous studies, and that determining these correlations will help decisions regarding adaptive re-planning (ART) aimed at reducing the delivered doses. Methods and Materials Prospective study: oropharyngeal cancer patients treated definitively with chemo-irradiation underwent daily cone beam CT (CBCT) with clinical set-up alignment based on C2 posterior edge. Parotid glands in the CBCTs were aligned by deformable registration to calculate cumulative delivered doses. Stimulated salivary flow rates were measured separately from each parotid gland pretherapy and periodically posttherapy. Results 36 parotid glands of 18 patients were analyzed. Average mean planned doses was 32 Gy and differences from planned to delivered mean gland doses were −4.9 to +8.4 Gy, median difference +2.2 Gy in glands whose delivered doses increased relative to planned. Both planned and delivered mean doses were significantly correlated with post-treatment salivary outputs at almost all post-therapy time points, without statistically significant differences in the correlations. Large dispersions [on average, standard deviation (SD) 3.6 Gy] characterized the dose/effect relationships for both. The differences between the cumulative delivered doses and planned doses were evident already at first fraction (r=0.92, p<0.0001) due to complex set-up deviations, e.g. rotations and neck articulations, uncorrected by the translational clinical alignments. Conclusions After daily translational set-up corrections, differences between planned and delivered doses in most glands were small relative to the SDs of the dose/saliva data, suggesting that ART is not likely to gain measurable salivary output improvement in most cases. These differences were observed already at first

  17. 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.

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

    SciTech Connect

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

    1987-05-01

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

  19. 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

  20. Dose responses of diamond detectors to monoenergetic X-rays

    NASA Astrophysics Data System (ADS)

    Yin, Z.; Hugtenburg, R. P.; Green, S.; Beddoe, A. H.

    2004-01-01

    The characterisation of a detectors response in the kilovoltage range is necessary to understand its response to scattered radiation in the megavoltage range. Scattered radiation is absorbed in the detector by the highly Z-dependent photoelectric process. Measurements of diamond detector response to highly filtered quasi-monoenergetic X-rays and synchrotron-generated monoenergetic photons have been performed revealing effects that relate to the presence of copper and silver used to form electrical contact with the crystal. A three-component model of energy absorption, utilizing tabulated cross-sections for C, Cu and Ag, is proposed and a calculation of phantom scatter factors for diamond detector is given.

  1. 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.

  2. Characterization of cure in model photocrosslinking acrylate systems: Relationships among tensile properties, Tg and ultraviolet dose

    SciTech Connect

    Rakas, M.A.

    1996-10-01

    The extent of cure of a thermosetting polymer is governed largely by polymerization kinetics and the difference between the polymerization temperature and the material`s ultimate glass transition temperature (Tg). For prepolymers which cure when exposed to ultraviolet (UV) radiation, other factors which strongly determine the extent of cure are the UV intensity and exposure time, and the interrelationship between the optical absorbance of the photoinitiator (PI) and the rate of formation of excited state PI radicals. Beers` Law can be used to understand the relationship between the PI`s molar absorptivity, its concentration, and adhesive film thickness. Many adhesives users are more concerned with bulk properties such as tensile modulus and Tg rather than a numerical measurement of degree of cure. Therefore, this research employed model acrylate formulations and determined changes in tensile properties and Tg as a function of film thickness and UV dose. These results enabled correlation of bulk and photoinitiator properties.

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

    EPA Science Inventory

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

  4. 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 ...

  5. 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...

  6. 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.)…

  7. RISK ASSESSMENT FOR CRYPTOSPORIDIUM: A HIERARCHICAL BAYESIAN ANALYSIS OF HUMAN DOSE-RESPONSE DATA. (R828035)

    EPA Science Inventory

    Three dose¯response studies were conducted with healthy volunteers using different Cryptosporidium parvum isolates (IOWA, TAMU, and UCP). The study data were previously analyzed for median infectious dose (ID50) using a simple cumulative perce...

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

    NASA Technical Reports Server (NTRS)

    Chappell, Lori J.; Cucinotta, Francis A.

    2010-01-01

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

  9. Relationship between histamine and physiological changes during the early response to nasal antigen provocation.

    PubMed

    Baroody, F M; Ford, S; Proud, D; Kagey-Sobotka, A; Lichtenstein, L; Naclerio, R M

    1999-02-01

    To investigate the temporal relationships of mediator release and physiological changes during the early response to allergen, we challenged allergic individuals intranasally with antigen and followed their responses. This was done by using small filter paper disks to challenge one nostril and collect secretions from both the challenged and the contralateral nostril, thus enabling us to evaluate the nasonasal reflex. There was a significant increase in sneezing after allergen challenge that peaked within 2 min and returned to baseline. The weights of nasal secretions as well as nasal symptoms increased immediately and remained significantly elevated for 20 min in both nostrils. Nasal airway resistance increased slowly, reaching its peak at approximately 6 min after challenge on the ipsilateral side, but it did not change on the contralateral side. Histamine levels peaked 30 s after removal of the allergen disk on the side of challenge, whereas albumin levels peaked after those of histamine. Lactoferrin paralleled the increase in secretion weights and occurred in both nostrils. Increasing doses of antigen produced dose-dependent increases in all parameters, whereas control challenges produced no response. These studies describe a human model for the evaluation of the allergic response that is capable of simultaneously measuring mediator release and the physiological response, including the nasonasal reflex. This model should prove useful in studying the mechanism of allergic rhinitis in humans. PMID:9931205

  10. 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.

  11. 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...

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

    EPA Science Inventory

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

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

    EPA Science Inventory

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

  14. A Comparison of Dose-Response Models for the Parotid Gland in a Large Group of Head-and-Neck Cancer Patients

    SciTech Connect

    Houweling, Antonetta C.; Philippens, Marielle E.P.; Dijkema, Tim; Roesink, Judith M.; Terhaard, Chris H.J.; Schilstra, Cornelis; Ten Haken, Randall K.; Eisbruch, Avraham; Raaijmakers, Cornelis P.J.

    2010-03-15

    Purpose: The dose-response relationship of the parotid gland has been described most frequently using the Lyman-Kutcher-Burman model. However, various other normal tissue complication probability (NTCP) models exist. We evaluated in a large group of patients the value of six NTCP models that describe the parotid gland dose response 1 year after radiotherapy. Methods and Materials: A total of 347 patients with head-and-neck tumors were included in this prospective parotid gland dose-response study. The patients were treated with either conventional radiotherapy or intensity-modulated radiotherapy. Dose-volume histograms for the parotid glands were derived from three-dimensional dose calculations using computed tomography scans. Stimulated salivary flow rates were measured before and 1 year after radiotherapy. A threshold of 25% of the pretreatment flow rate was used to define a complication. The evaluated models included the Lyman-Kutcher-Burman model, the mean dose model, the relative seriality model, the critical volume model, the parallel functional subunit model, and the dose-threshold model. The goodness of fit (GOF) was determined by the deviance and a Monte Carlo hypothesis test. Ranking of the models was based on Akaike's information criterion (AIC). Results: None of the models was rejected based on the evaluation of the GOF. The mean dose model was ranked as the best model based on the AIC. The TD{sub 50} in these models was approximately 39 Gy. Conclusions: The mean dose model was preferred for describing the dose-response relationship of the parotid gland.

  15. Large Cohort Dose-Volume Response Analysis of Parotid Gland Function After Radiotherapy: Intensity-Modulated Versus Conventional Radiotherapy

    SciTech Connect

    Dijkema, Tim Terhaard, Chris H.J.; Roesink, Judith M.; Braam, Petra M.; Gils, Carla H. van; Moerland, Marinus A.; Raaijmakers, Cornelis P.J.

    2008-11-15

    Purpose: To compare parotid gland dose-volume response relationships in a large cohort of patients treated with intensity-modulated (IMRT) and conventional radiotherapy (CRT). Methods and materials: A total of 221 patients (64 treated with IMRT, 157 with CRT) with various head-and-neck malignancies were prospectively evaluated. The distribution of tumor subsites in both groups was unbalanced. Stimulated parotid flow rates were measured before and 6 weeks, 6 months, and 1 year after radiotherapy. Parotid gland dose-volume histograms were derived from computed tomography-based treatment planning. The normal tissue complication probability (NTCP) model proposed by Lyman was fit to the data. A complication was defined as stimulated parotid flow ratio <25% of the pretreatment flow rate. The relative risk of complications was determined for IMRT vs. CRT and adjusted for the mean parotid gland dose using Poisson regression modeling. Results: One year after radiotherapy, NTCP curves for IMRT and CRT were comparable with a TD{sub 50} (uniform dose leading to a 50% complication probability) of 38 and 40 Gy, respectively. Until 6 months after RT, corrected for mean dose, different complication probabilities existed for IMRT vs. CRT. The relative risk of a complication for IMRT vs. CRT after 6 weeks was 1.42 (95% CI 1.21-1.67), after 6 months 1.41 (95% CI; 1.12-1.77), and at 1 year 1.21 (95% CI 0.87-1.68), after correcting for mean dose. Conclusions: One year after radiotherapy, no difference existed in the mean dose-based NTCP curves for IMRT and CRT. Early after radiotherapy (up to 6 months) mean dose based (Lyman) models failed to fully describe the effects of radiotherapy on the parotid glands.

  16. Liposomal Amphotericin B and Leishmaniasis: Dose and Response

    PubMed Central

    Sundar, Shyam; Chakravarty, Jaya

    2010-01-01

    Liposomal amphotericin B has been used with increasing frequency to treat visceral leishmaniasis (VL). It is the treatment of choice for immunocompetent patients in the Mediterranean region and the preferred drug for HIV/VL co-infection. Although there is a regional variation in the susceptibility of the parasite a total dose of 20 mg/kg is effective in immunocompetent patients. Randomized clinical trials of liposomal amphotericin B in the treatment and secondary prophylaxis of HIV-VL coinfected patients is urgently needed to optimize treatment in this subset. With the availability of Liposomal amphotericin B at a preferential pricing in the endemic areas, short course combination therapy can become a viable alternative. PMID:20606972

  17. Demonstration of an adaptive response to preconditioning Frankliniella occidentalis (Pergande) to sublethal doses of spinosad: a hormetic-dose response.

    PubMed

    Gong, Youhui; Xu, Baoyun; Zhang, Youjun; Gao, Xiwu; Wu, Qingjun

    2015-07-01

    Sublethal doses of some insecticides have been reported to either stimulate or reduce the survival and fecundity of insects. Many sublethal-effect studies have been conducted after exposure of only one generation to sublethal insecticides, and there is little information about the sublethal effects on insects after long-term exposure to sublethal insecticides. In this study, changes in biological characteristics were investigated in spinosad-susceptible (Spin-S) and sublethal-spinosad-treated (Spin-Sub) strains of Frankliniella occidentalis (Pergande) after exposure to their corresponding sublethal concentrations of spinosad. The results showed that for the Spin-S strain, the LC10 concentration of spinosad slightly affected the biotic fitness both in parents and offspring of F. occidentalis. The LC25 concentration of spinosad prolonged the development time, reduced the fecundity, and significantly reduced the intrinsic rate of increase, the net reproductive rate and the finite rate of increase in the Spin-S strain. However, the negative effects were not as pronounced in the offspring (F1 generation) as in the parent generation. For the Spin-Sub strain, the LC10 and LC25 concentrations of spinosad had little negative effect on the development and fecundity, and no significant difference was found between the effects of the LC10 and LC25 treatments on the Spin-Sub strain. The Spin-Sub strain exhibited a shorter developmental time, and larger intrinsic rates of increase and net reproductive rates, compared with the corresponding treatments of the Spin-S strain. These findings combined with our previous studies suggest that the biotic fitness increased in the Spin-Sub strain and the strain became more adaptable to sublethal doses of spinosad, compared with the Spin-S strain. Physiological and biochemical adaptation may contribute to these changes after long treatment times at sublethal doses. PMID:25910608

  18. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors.

    PubMed

    Chou, T C; Talalay, P

    1984-01-01

    A generalized method for analyzing the effects of multiple drugs and for determining summation, synergism and antagonism has been proposed. The derived, generalized equations are based on kinetic principles. The method is relatively simple and is not limited by whether the dose-effect relationships are hyperbolic or sigmoidal, whether the effects of the drugs are mutually exclusive or nonexclusive, whether the ligand interactions are competitive, noncompetitive or uncompetitive, whether the drugs are agonists or antagonists, or the number of drugs involved. The equations for the two most widely used methods for analyzing synergism, antagonism and summation of effects of multiple drugs, the isobologram and fractional product concepts, have been derived and been shown to have limitations in their applications. These two methods cannot be used indiscriminately. The equations underlying these two methods can be derived from a more generalized equation previously developed by us (59). It can be shown that the isobologram is valid only for drugs whose effects are mutually exclusive, whereas the fractional product method is valid only for mutually nonexclusive drugs which have hyperbolic dose-effect curves. Furthermore, in the isobol method, it is laborious to find proper combinations of drugs that would produce an iso-effective curve, and the fractional product method tends to give indication of synergism, since it underestimates the summation of the effect of mutually nonexclusive drugs that have sigmoidal dose-effect curves. The method described herein is devoid of these deficiencies and limitations. The simplified experimental design proposed for multiple drug-effect analysis has the following advantages: It provides a simple diagnostic plot (i.e., the median-effect plot) for evaluating the applicability of the data, and provides parameters that can be directly used to obtain a general equation for the dose-effect relation; the analysis which involves logarithmic

  19. Dose-response evaluation of Veratrum californicum in sheep

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Veratrum californicum was discovered to be teratogenic in sheep over 50 years ago. The alkaloids in V. californicum responsible for terata induction are jervine, 11-deoxojervine (cyclopamine), and cycloposine (the glycoside of cyclopamine). Current research objectives are to better describe cyclop...

  20. DOSE-DEPENDENT ALLERGIC ASTHMA RESPONSES TO PENICILLIUM CHRYSOGENUM

    EPA Science Inventory

    ABSTRACT
    Indoor mold has been associated with development of allergic asthma. Penicillium chrysogenum, a common indoor mold, is known to have several allergens and its viable conidia can induce allergic responses in a mouse model of allergic penicilliosis. The hypothesis o...

  1. Low-dose radiation exposure induces a HIF-1-mediated adaptive and protective metabolic response

    PubMed Central

    Lall, R; Ganapathy, S; Yang, M; Xiao, S; Xu, T; Su, H; Shadfan, M; Asara, J M; Ha, C S; Ben-Sahra, I; Manning, B D; Little, J B; Yuan, Z-M

    2014-01-01

    Because of insufficient understanding of the molecular effects of low levels of radiation exposure, there is a great uncertainty regarding its health risks. We report here that treatment of normal human cells with low-dose radiation induces a metabolic shift from oxidative phosphorylation to aerobic glycolysis resulting in increased radiation resistance. This metabolic change is highlighted by upregulation of genes encoding glucose transporters and enzymes of glycolysis and the oxidative pentose phosphate pathway, concomitant with downregulation of mitochondrial genes, with corresponding changes in metabolic flux through these pathways. Mechanistically, the metabolic reprogramming depends on HIF1α, which is induced specifically by low-dose irradiation linking the metabolic pathway with cellular radiation dose response. Increased glucose flux and radiation resistance from low-dose irradiation are also observed systemically in mice. This highly sensitive metabolic response to low-dose radiation has important implications in understanding and assessing the health risks of radiation exposure. PMID:24583639

  2. Community response to noise in Vietnam: exposure-response relationships based on the community tolerance level.

    PubMed

    Gjestland, Truls; Nguyen, Thu Lan; Yano, Takashi

    2015-05-01

    Social surveys on noise annoyance have been conducted in five different cities in Vietnam. The surveys included both aircraft noise (three airports) and road traffic noise (five cities). The main objective for these studies was to establish dose-response functions that were representative for Vietnam. The results have been compared with results from similar surveys from other regions. Dose-response functions for aircraft noise in Vietnam showing the percentage of highly annoyed people versus the noise level are nearly identical to those presented in the European Noise Directive [European Commission (2002). http://ec.europa.eu/environment/noise/directive.htm]. For road traffic noise, however, the results indicate that people in Vietnam are more tolerant. The noise levels can be increased by 5-10 dB in order to have a response similar to the curve recommended by the European Commission. PMID:25994692

  3. 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.

  4. Iron Oxide Nanoparticle Agglomeration Influences Dose-Rates and Modulates Oxidative Stress Mediated Dose-Response Profiles In Vitro

    SciTech Connect

    Sharma, Gaurav; Kodali, Vamsi K.; Gaffrey, Matthew J.; Wang, Wei; Minard, Kevin R.; Karin, Norman J.; Teeguarden, Justin G.; Thrall, Brian D.

    2013-07-31

    Spontaneous agglomeration of engineered nanoparticles (ENPs) is a common problem in cell culture media which can confound interpretation of in vitro nanotoxicity studies. The authors created stable agglomerates of iron oxide nanoparticles (IONPs) in conventional culture medium, which varied in hydrodynamic size (276 nm-1.5 μm) but were composed of identical primary particles with similar surface potentials and protein coatings. Studies using C10 lung epithelial cells show that the dose rate effects of agglomeration can be substantial, varying by over an order of magnitude difference in cellular dose in some cases. Quantification by magnetic particle detection showed that small agglomerates of carboxylated IONPs induced greater cytotoxicity and redox-regulated gene expression when compared with large agglomerates on an equivalent total cellular IONP mass dose basis, whereas agglomerates of amine-modified IONPs failed to induce cytotoxicity or redox-regulated gene expression despite delivery of similar cellular doses. Dosimetry modelling and experimental measurements reveal that on a delivered surface area basis, large and small agglomerates of carboxylated IONPs have similar inherent potency for the generation of ROS, induction of stress-related genes and eventual cytotoxicity. The results suggest that reactive moieties on the agglomerate surface are more efficient in catalysing cellular ROS production than molecules buried within the agglomerate core. Because of the dynamic, size and density-dependent nature of ENP delivery to cells in vitro, the biological consequences of agglomeration are not discernible from static measures of exposure concentration (μg/ml) alone, highlighting the central importance of integrated physical characterisation and quantitative dosimetry for in vitro studies. The combined experimental and computational approach provides a quantitative framework for evaluating relationships between the biocompatibility of nanoparticles and their

  5. 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

  6. A Raman spectroscopic study of cell response to clinical doses of ionizing radiation.

    PubMed

    Harder, Samantha J; Matthews, Quinn; Isabelle, Martin; Brolo, Alexandre G; Lum, Julian J; Jirasek, Andrew

    2015-01-01

    The drive toward personalized radiation therapy (RT) has created significant interest in determining patient-specific tumor and normal tissue responses to radiation. Raman spectroscopy (RS) is a non-invasive and label-free technique that can detect radiation response through assessment of radiation-induced biochemical changes in tumor cells. In the current study, single-cell RS identified specific radiation-induced responses in four human epithelial tumor cell lines: lung (H460), breast (MCF-7, MDA-MB-231), and prostate (LNCaP), following exposure to clinical doses of radiation (2-10 Gy). At low radiation doses (2 Gy), H460 and MCF-7 cell lines showed an increase in glycogen-related spectral features, and the LNCaP cell line showed a membrane phospholipid-related radiation response. In these cell lines, only spectral information from populations receiving 10 Gy or less was required to identify radiation-related features using principal component analysis (PCA). In contrast, the MDA-MB-231 cell line showed a significant increase in protein relative to nucleic acid and lipid spectral features at doses of 6 Gy or higher, and high-dose information (30, 50 Gy) was required for PCA to identify this biological response. The biochemical nature of the radiation-related changes occurring in cells exposed to clinical doses was found to segregate by status of p53 and radiation sensitivity. Furthermore, the utility of RS to identify a biological response in human tumor cells exposed to therapeutic doses of radiation was found to be governed by the extent of the biochemical changes induced by a radiation response and is therefore cell line specific. The results of this study demonstrate the utility and effectiveness of single-cell RS to identify and measure biological responses in tumor cells exposed to standard radiotherapy doses. PMID:25588147

  7. Salmonella Fecal Shedding and Immune Responses are Dose- and Serotype- Dependent in Pigs

    PubMed Central

    Ivanek, Renata; Österberg, Julia; Gautam, Raju; Sternberg Lewerin, Susanna

    2012-01-01

    Despite the public health importance of Salmonella infection in pigs, little is known about the associated dynamics of fecal shedding and immunity. In this study, we investigated the transitions of pigs through the states of Salmonella fecal shedding and immune response post-Salmonella inoculation as affected by the challenge dose and serotype. Continuous-time multistate Markov models were developed using published experimental data. The model for shedding had four transient states, of which two were shedding (continuous and intermittent shedding) and two non-shedding (latency and intermittent non-shedding), and one absorbing state representing permanent cessation of shedding. The immune response model had two transient states representing responses below and above the seroconversion level. The effects of two doses [low (0.65×106 CFU/pig) and high (0.65×109 CFU/pig)] and four serotypes (Salmonella Yoruba, Salmonella Cubana, Salmonella Typhimurium, and Salmonella Derby) on the models' transition intensities were evaluated using a proportional intensities model. Results indicated statistically significant effects of the challenge dose and serotype on the dynamics of shedding and immune response. The time spent in the specific states was also estimated. Continuous shedding was on average 10–26 days longer, while intermittent non-shedding was 2–4 days shorter, in pigs challenged with the high compared to low dose. Interestingly, among pigs challenged with the high dose, the continuous and intermittent shedding states were on average up to 10–17 and 3–4 days longer, respectively, in pigs infected with S. Cubana compared to the other three serotypes. Pigs challenged with the high dose of S. Typhimurium or S. Derby seroconverted on average up to 8–11 days faster compared to the low dose. These findings highlight that Salmonella fecal shedding and immune response following Salmonella challenge are dose- and serotype-dependent and that the detection of specific

  8. Dose and developmental responses of Anopheles merus larvae to salinity

    PubMed Central

    White, Bradley J.; Kundert, Peter N.; Turissini, David A.; Van Ekeris, Leslie; Linser, Paul J.; Besansky, Nora J.

    2013-01-01

    SUMMARY Saltwater tolerance is a trait that carries both ecological and epidemiological significance for Anopheles mosquitoes that transmit human malaria, as it plays a key role in determining their habitat use and ecological distribution, and thus their local contribution to malaria transmission. Here, we lay the groundwork for genetic dissection of this trait by quantifying saltwater tolerance in three closely related cryptic species and malaria vectors from the Afrotropical Anopheles gambiae complex that are known to differ starkly in their tolerance to salinity: the obligate freshwater species A. gambiae and A. coluzzii, and the saltwater-tolerant species A. merus. We performed detailed comparisons of survivorship under varying salinities, using multiple strains of A. gambiae, A. coluzzii and A. merus, as well as F1 progeny from reciprocal crosses of A. merus and A. coluzzii. Additionally, using immunohistochemistry, we compared the location of three ion regulatory proteins (Na+/K+-ATPase, carbonic anhydrase and Na+/H+-antiporter) in the recta of A. coluzzii and A. merus reared in freshwater or saline water. As expected, we found that A. merus survives exposure to high salinities better than A. gambiae and A. coluzzii. Further, we found that exposure to a salinity level of 15.85 g NaCl l−1 is a discriminating dose that kills all A. gambiae, A. coluzzii and A. coluzzii–A. merus F1 larvae, but does not negatively impact the survival of A. merus. Importantly, phenotypic expression of saltwater tolerance by A. merus is highly dependent upon the developmental time of exposure, and based on immunohistochemistry, salt tolerance appears to involve a major shift in Na+/K+-ATPase localization in the rectum, as observed previously for the distantly related saline-tolerant species A. albimanus. PMID:23966587

  9. Dose-response effects of fluoride in mammalian species

    SciTech Connect

    Smith, F.A.

    1983-01-01

    A number of deleterious effects have been attributed to the ingestion of fluoride, sometimes for good reason and sometimes with no good basis. Literature describing some of these effects has been reviewed and threshold doses for the effects are suggested. Fluoride absorbed into the systemic circulation is rapidly removed, in part by storage in the skeletal system and in part by excretion in the urine. Skeletal storage evident in x-ray films as increased density to the x-rays is seen in about 10% of persons who have used drinking water containing 8 mg F per liter (8 ppm) for long periods of time. No deleterious effects are seen at this level of F storage in the bone. In the kidney the renal status of a population using water containing 8 mg F was not different from that of a population in an area where there was 0.4 ppm F in the water supply. Decreased renal function has been reported in persons using water supplies containing 10 ppm F. In human subjects growth is unaffected by prolonged use of water supplies containing up to 6-8 mg F/l (6-8 ppm). Growth in most animal species is not affected at concentrations of 100 mg F/kg diet (100 ppm). However, cattle undergoing cycle pregnancy, gestation and lactation appear to be more sensitive and growth is adversely affected at more than 40 ppm F in the diet. For cardiovascular effects, prolonged use of a water supply containing 2.5 mg F/l (2.5 ppm) was found not to increase the incidence of CVD.

  10. Dose and developmental responses of Anopheles merus larvae to salinity.

    PubMed

    White, Bradley J; Kundert, Peter N; Turissini, David A; Van Ekeris, Leslie; Linser, Paul J; Besansky, Nora J

    2013-09-15

    Saltwater tolerance is a trait that carries both ecological and epidemiological significance for Anopheles mosquitoes that transmit human malaria, as it plays a key role in determining their habitat use and ecological distribution, and thus their local contribution to malaria transmission. Here, we lay the groundwork for genetic dissection of this trait by quantifying saltwater tolerance in three closely related cryptic species and malaria vectors from the Afrotropical Anopheles gambiae complex that are known to differ starkly in their tolerance to salinity: the obligate freshwater species A. gambiae and A. coluzzii, and the saltwater-tolerant species A. merus. We performed detailed comparisons of survivorship under varying salinities, using multiple strains of A. gambiae, A. coluzzii and A. merus, as well as F1 progeny from reciprocal crosses of A. merus and A. coluzzii. Additionally, using immunohistochemistry, we compared the location of three ion regulatory proteins (Na(+)/K(+)-ATPase, carbonic anhydrase and Na(+)/H(+)-antiporter) in the recta of A. coluzzii and A. merus reared in freshwater or saline water. As expected, we found that A. merus survives exposure to high salinities better than A. gambiae and A. coluzzii. Further, we found that exposure to a salinity level of 15.85 g NaCl l(-1) is a discriminating dose that kills all A. gambiae, A. coluzzii and A. coluzzii-A. merus F1 larvae, but does not negatively impact the survival of A. merus. Importantly, phenotypic expression of saltwater tolerance by A. merus is highly dependent upon the developmental time of exposure, and based on immunohistochemistry, salt tolerance appears to involve a major shift in Na(+)/K+-ATPase localization in the rectum, as observed previously for the distantly related saline-tolerant species A. albimanus. PMID:23966587

  11. 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

  12. The road to embryologically based dose-response models.

    PubMed Central

    Kavlock, R J; Setzer, R W

    1996-01-01

    The goal of researchers working in the area of developmental toxicology is to prevent adverse reproductive outcomes (early pregnancy loss, birth defects, reduced birth weight, and altered functional development) in humans due to exposures to environmental contaminants, therapeutic drugs, and other factors. To best achieve that goal, it is important that relevant information be gathered and assimilated in the risk assessment process. One of the major challenges of improved risk assessment is to better use all pertinent biological and mechanistic information. This may be done qualitatively (e.g., demonstrating that the experimental model is not appropriate for extrapolation purposes); semiquantitatively (using information to reduce the degree of uncertainty present under default extrapolation procedures), or quantitatively (formally describing the relationships between exposure and adverse outcome in mathematical forms, including components that directly reflect individual steps in the overall progression of toxicity). In this paper we review the recent advances in the risk assessment process for developmental toxicants and hypothesize on future directions that may revolutionize our thinking in this area. The road to these changes sometimes appears to be a well-mapped course on a relatively smooth surface; at other times the path is bumpy and obscure, while at still other times it is only a wish in the eye of the engineer to cross an uncharted and rugged environment. Images Figure 11. A Figure 11. B PMID:8722115

  13. Relationships between exposure and dose in aquatic toxicity tests for organic chemicals.

    PubMed

    Mackay, Donald; McCarty, Lynn S; Arnot, Jon A

    2014-09-01

    There is continuing debate about the merits of exposure-based toxicity metrics such as median lethal concentration (LC50) versus organism-based metrics such as critical body residue (CBR) as indicators of chemical toxicity to aquatic organisms. To demonstrate relationships and differences between these 2 metrics, the authors applied a simple one-compartment toxicokinetic mass-balance model for water-exposed fish for a series of hypothetical organic chemicals exhibiting baseline narcotic toxicity. The authors also considered the influence of several toxicity-modifying factors. The results showed that the results of standard toxicity tests, such as the LC50, are strongly influenced by several modifying factors, including chemical and organism characteristics such as hydrophobicity, body size, lipid content, metabolic biotransformation, and exposure durations. Consequently, reported LC50s may not represent consistent dose surrogates and may be inappropriate for comparing the relative toxicity of chemicals. For comparisons of toxicity between chemicals, it is preferable to employ a delivered dose metric, such as the CBR. Reproducible toxicity data for a specific combination of chemical, exposure conditions, and organism can be obtained only if the extent of approach to steady state is known. Suggestions are made for revisions in test protocols, including the use of models in advance of empirical testing, to improve the efficiency and effectiveness of tests and reduce the confounding influences of toxicity-modifying factors, especially exposure duration and metabolic biotransformation. This will assist in linking empirical measurements of LC50s and CBRs, 2 different but related indicators of aquatic toxicity, and thereby improve understanding of the large existing database of aquatic toxicity test results. PMID:24889496

  14. Response of Brazilian native trees to acute ozone dose.

    PubMed

    Moura, Bárbara Baêsso; de Souza, Sílvia Ribeiro; Alves, Edenise Segala

    2014-03-01

    Ozone (O3) is a toxic secondary pollutant able to cause an intense oxidative stress that induces visual symptoms on sensitive plant species. Controlled fumigation experiment was conducted with the aim to verify the O3 sensibility of three tropical species: Piptadenia gonoachanta (Mart.) Macbr. (Fabaceae), Astronium graveolens Jacq. (Anacardiaceae), and Croton floribundus Spreng. (Euphorbiaceae). The microscopical features involved in the oxidative stress were recognized based on specific histochemical analysis. The three species showed visual symptoms, characterized as necrosis and stippling between the veins, mostly visible on the adaxial leaf surface. All the studied species presented hypersensitive-like response (HR-like), and peroxide hydrogen accumulation (H2O2) followed by cell death and proanthocyanidin oxidation in P. gonoachanta and A. graveolens. In P. gonoachanta, a decrease in chlorophyll autofluorescence occurred on symptomatic tissues, and in A. graveolens and C. floribundus, a polyphenol compound accumulation occurred. The responses of Brazilian native species were similar to those described for sensitive species from temperate climate, and microscopical markers may be useful for the detection of ozone symptoms in future studies in the field. PMID:24297466

  15. Relationships between rating scales, question stem wording, and community responses to railway noise

    NASA Astrophysics Data System (ADS)

    Sato, Tetsumi; Yano, Takashi; Morihara, Takashi; Masden, Kirk

    2004-10-01

    Two series of social surveys on community responses to railway noise were carried out in Japan to evaluate the relationships between two verbal scales and a numeric scale, and those among four base descriptors. In the first survey, two types of questionnaires were prepared in which a 0-10- point numeric scale was used in combination with either a four-point or a five-point verbal scale. The key questions concerned annoyance, activity disturbance and related effects caused by railway noise. Community responses were compared on the basis of the dose-response relationships. Regarding the percentages of respondents who answered, "highly annoyed," it was found that there were no systematic differences between the two verbal scales. It was also found that the extent of noise annoyance rated on the four-point or five-point verbal scale corresponded with that rated on the 11-point numeric scale by percentages of scale steps. In the second survey, four types of questionnaires were prepared, each using one of the four base descriptors. Community responses to general noise annoyance among the four base descriptors were compared. No systematic differences were found among the four base descriptors.

  16. Low Dose Studies with Focused X-rays in Cell and Tissue Models: Mechanisms of Bystander and Genomic Instability Responses

    SciTech Connect

    Barry D. Michael; Kathryn Held; Kevin Prise

    2002-12-19

    of the relationship between high- and low-dose exposures. The targeting approach also allows us to study very clearly a newly recognized effect of radiation, the ''bystander effect'', which appears to dominate some low-dose responses and therefore may have a significant role in low-dose risk mechanisms. Our project also addresses the concept that the background of naturally occurring oxidative damage that takes place continually in cells due to byproducts of metabolism may play a role in treatments that modify the levels of oxidative damage, either alone or in combination with low-dose irradiation. In this project, we have used human and rodent cell lines and each set of experiments has been carried out on a single cell type. However, low-dose research has to extend into tissues because signaling between cells of different types is likely to influence the responses. Our studies have therefore also included microbeam experiments using a model tissue system that consists of an explant of a small piece of pig ureter grown in culture. The structure of this tissue is similar to that of epithelium and there it relates to the tissues in which carcinoma arises. Our studies have been able to measure bystander-induced changes in the cells growing out from the tissue fragment after it has been targeted with a few radiation tracks to mimic a low-dose exposure.

  17. PHA-stimulated immune-responsiveness in mercury-dosed zebra finches does not match results from environmentally exposed songbirds.

    PubMed

    Caudill, Mitchell T; Spear, Eliza L; Varian-Ramos, Claire W; Cristol, Daniel A

    2015-04-01

    Dietary mercury exposure is associated with suppressed immune responsiveness in birds. This study examined the immune-responsiveness of domestic zebra finches (Taeniopygia guttata) experimentally exposed to mercury through their diet. We used the phytohemagglutinin (PHA) skin-swelling test to assay the effect of two modes of mercury exposure. Some finches received exposure to mercury only after reaching sexual maturity, while others were maintained on a mercury-dosed diet throughout life, including development. Each bird received one of five dietary concentrations of methylmercury cysteine (0.0, 0.3, 0.6, 1.2 or 2.4 ppm). In contrast to a study on wild songbirds at a mercury-contaminated site, we detected no relationship between mercury level and immunological response to PHA, regardless of mode of exposure. This result represents the first major difference found by our laboratory between wild birds exposed to environmental mercury and captive birds experimentally exposed to mercury. PMID:25638440

  18. Comparing intraspecific responses of 12 winter wheat cultivars to different doses of ultraviolet-B radiation.

    PubMed

    Lv, Zhiwei; Zhang, Xiusheng; Liu, Like; Guo, Yan; Fan, Yinglun; Yang, Xiaoyan; Li, Yuxia; Zhang, Wenhui

    2013-02-01

    In this study, intraspecific responses of 12 winter wheat cultivars to different doses of ultraviolet-B radiation (UV-B) were analyzed and compared. The results showed that the low UV-B dose of 3.24kJm(-2)d(-1) generally inhibited the plant height, but promoted the dry weight and photochemical reflectance index (PRI). The high UV-B dose of 5.40kJm(-2)d(-1) inhibited most of the indexes, especially plant height and fresh weight. Under the treatments of two UV-B doses, the response indexes (RIs) of plant height, dry weight, fresh weight, carotenoid, and anthocyanin were all significantly correlated with the cumulative stress response index (CSRI). The RIs of carotenoid and anthocyanin exhibited higher correlations with dry weight and fresh weight, indicating that these indexes were vital to UV-B tolerance. By comparing the correlations of the seven indexes between two doses of UV-B radiation, the responses of 12 cultivars' plant height and dry weight to different doses of UV-B were very significant (P<0.01). Thus, when comparing the UV-B tolerance of different winter wheat seedlings, no matter using high dose or low dose UV-B, the index of plant height should be concerned first and dry weight could be used secondarily. Among 12 winter wheat cultivars, Nongda 6081 exhibited significant resistance to two doses of UV-B radiation while others were variable. Differences in the accumulation of UV-absorbing compounds induced by UV-B in leaves may be the main and direct reason for the intraspecific differences between resistant and sensitive cultivars. PMID:23280246

  19. 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

  20. 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...

  1. 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:…

  2. AN EXTRACT OF PENICILLIUM CHRYSOGENUM INDUCES DOSE-DEPENDENT ALLERGIC ASTHMA RESPONSES IN MICE

    EPA Science Inventory

    Rationale: Penicillium chrysogenum, a common indoor mold, is known to have several allergens and can induce allergic responses in a mouse model of allergic penicilliosis. Our hypothesis is that soluble components of P. chrysogenum (PCE) can dose-dependently induce responses typ...

  3. Dose-Response Evaluation of Braslet-M Occlusion Cuffs

    NASA Technical Reports Server (NTRS)

    Ebert, Douglas; Garcia, Kathleen; Sargsyan, Ashot E.; Ham, David; Hamilton, Douglas; Dulchavsky, Scott A.

    2010-01-01

    Introduction: Braslet-M is a set of special elasticized thigh cuffs used by the Russian space agency to reduce the effects of the head-ward fluid shift during early adaptation to microgravity by sequestering fluid in the lower extremities. Currently, no imaging modalities are used in the calibration of the device, and the pressure required to produce a predictable physiological response is unknown. This investigation intends to relate the pressure exerted by the cuffs to the extent of fluid redistribution and commensurate physiological effects. Materials and Methods: Ten healthy subjects with standardized fluid intake participated in the study. Data collection included femoral and internal jugular vein imaging in two orthogonal planes, pulsed Doppler of cervical and femoral vessels and middle cerebral artery, optic nerve imaging, and echocardiography. Braslet-M cuff pressure was monitored at the skin interface using pre-calibrated pressure sensors. Using 6 and 30 head-down tilt in two separate sessions, the effect of Braslet-M was assessed while incrementally tightening the cuffs. Cuffs were then simultaneously released to document the resulting hemodynamic change. Results: Preliminary analysis shows correlation between physical pressure exerted by the Braslet-M device and several parameters such as jugular and femoral vein cross-sections, resistivity of the lower extremity vascular bed, and others. A number of parameters reflect blood redistribution and will be used to determine the therapeutic range of the device and to prevent unsafe application. Conclusion: Braslet-M exerts a physical effect that can be measured and correlated with many changes in central and peripheral hemodynamics. Analysis of the full data set will be required to make definitive recommendations regarding the range of safe therapeutic application. Objective data and subjective responses suggest that a safer and equally effective use of Braslet can be achieved when compared with the current

  4. 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.

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    1987-03-01

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

  7. Defining the Optimal Selenium Dose for Prostate Cancer Risk Reduction: Insights from the U-Shaped Relationship between Selenium Status, DNA Damage, and Apoptosis.

    PubMed

    Chiang, Emily C; Shen, Shuren; Kengeri, Seema S; Xu, Huiping; Combs, Gerald F; Morris, J Steven; Bostwick, David G; Waters, David J

    2009-01-01

    Our work in dogs has revealed a U-shaped dose response between selenium status and prostatic DNA damage that remarkably parallels the relationship between dietary selenium and prostate cancer risk in men, suggesting that more selenium is not necessarily better. Herein, we extend this canine work to show that the selenium dose that minimizes prostatic DNA damage also maximizes apoptosis-a cancer-suppressing death switch used by prostatic epithelial cells. These provocative findings suggest a new line of thinking about how selenium can reduce cancer risk. Mid-range selenium status (.67-.92 ppm in toenails) favors a process we call "homeostatic housecleaning"-an upregulated apoptosis that preferentially purges damaged prostatic cells. Also, the U-shaped relationship provides valuable insight into stratifying individuals as selenium-responsive or selenium-refractory, based upon the likelihood of reducing their cancer risk by additional selenium. By studying elderly dogs, the only non-human animal model of spontaneous prostate cancer, we have established a robust experimental approach bridging the gap between laboratory and human studies that can help to define the optimal doses of cancer preventives for large-scale human trials. Moreover, our observations bring much needed clarity to the null results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) and set a new research priority: testing whether men with low, suboptimal selenium levels less than 0.8 ppm in toenails can achieve cancer risk reduction through daily supplementation. PMID:20877485

  8. Is the assumption of normality or log-normality for continuous response data critical for benchmark dose estimation?

    SciTech Connect

    Shao, Kan; Gift, Jeffrey S.; Setzer, R. Woodrow

    2013-11-01

    Continuous responses (e.g. body weight) are widely used in risk assessment for determining the benchmark dose (BMD) which is used to derive a U.S. EPA reference dose. One critical question that is not often addressed in dose–response assessments is whether to model the continuous data as normally or log-normally distributed. Additionally, if lognormality is assumed, and only summarized response data (i.e., mean ± standard deviation) are available as is usual in the peer-reviewed literature, the BMD can only be approximated. In this study, using the “hybrid” method and relative deviation approach, we first evaluate six representative continuous dose–response datasets reporting individual animal responses to investigate the impact on BMD/BMDL estimates of (1) the distribution assumption and (2) the use of summarized versus individual animal data when a log-normal distribution is assumed. We also conduct simulation studies evaluating model fits to various known distributions to investigate whether the distribution assumption has influence on BMD/BMDL estimates. Our results indicate that BMDs estimated using the hybrid method are more sensitive to the distribution assumption than counterpart BMDs estimated using the relative deviation approach. The choice of distribution assumption has limited impact on the BMD/BMDL estimates when the within dose-group variance is small, while the lognormality assumption is a better choice for relative deviation method when data are more skewed because of its appropriateness in describing the relationship between mean and standard deviation. Additionally, the results suggest that the use of summarized data versus individual response data to characterize log-normal distributions has minimal impact on BMD estimates. - Highlights: • We investigate to what extent the distribution assumption can affect BMD estimates. • Both real data analysis and simulation study are conducted. • BMDs estimated using hybrid method are more

  9. CCL2 mediates the circadian response to low dose endotoxin.

    PubMed

    Duhart, José M; Brocardo, Lucila; Mul Fedele, Malena L; Guglielmotti, Angelo; Golombek, Diego A

    2016-09-01

    The mammalian circadian system is mainly originated in a master oscillator located in the suprachiasmatic nuclei (SCN) in the hypothalamus. Previous reports from our and other groups have shown that the SCN are sensitive to systemic immune activation during the early night, through a mechanism that relies on the action of proinflammatory factors within this structure. Chemokine (C-C motif) ligand 2 (CCL2) is induced in the brain upon peripheral immune activation, and it has been shown to modulate neuronal physiology. In the present work we tested whether CCL2 might be involved in the response of the circadian clock to peripheral endotoxin administration. The CCL2 receptor, C-C chemokine receptor type 2 (CCR2), was detected in the SCN of mice, with higher levels of expression during the early night, when the clock is sensitive to immune activation. Ccl2 was induced in the SCN upon intraperitoneal lipopolysaccharide (LPS) administration. Furthermore, mice receiving an intracerebroventricular (Icv) administration of a CCL2 synthesis inhibitor (Bindarit), showed a reduction LPS-induced circadian phase changes and Icv delivery of CCL2 led to phase delays in the circadian clock. In addition, we tested the possibility that CCL2 might also be involved in the photic regulation of the clock. Icv administration of Bindarit did not modify the effects of light pulses on the circadian clock. In summary, we found that CCL2, acting at the SCN level is important for the circadian effects of immune activation. PMID:27178133

  10. Relationship between DMS concentration and the upper mixed layer solar radiation dose

    NASA Astrophysics Data System (ADS)

    Belviso, S.; Caniaux, G.

    2009-04-01

    Dimethylsulfide (DMS) is a natural sulfur compound arising from algal dimethylsulfoniopropionate (DMSP) but through complex biotic and abiotic processes. It is an important natural source of atmospheric sulfur providing new and/or bigger hygroscopic particles for cloud formation over the ocean. One recent study (Vallina and Simo, Science, 2007) suggests the existence of a close quantitative link, at the global scale but also locally, between DMS and the solar radiation dose (SRD), a measure of available radiation inside the mixed layer. Joint data including CTDs, DMS concentration and solar radiation data, collected all along the year 2001 in the northeastern Atlantic during the POMME experiment are analyzed. Contrary to the observations in the Sargasso Sea and Blanes Bay (Mediterranean Sea) presented by Vallina and Simo (2007), this new data set clearly indicates that SRD and DMS are only weakly correlated, and this whatever the numerous sensitivity tests performed (i.e. the solar irradiance, the optical properties of surface waters, the mixed layer depth criteria). Additionally, the DMS versus SRD relationship appears quite sensitive to the irradiance attenuation law. Hence, it appears that SRD cannot be used to understand DMS dynamics at the scale of the north Atlantic basin.

  11. Pilot study about dose-effect relationship of ocular injury in argon laser photocoagulation

    NASA Astrophysics Data System (ADS)

    Chen, P.; Zhang, C. P.; Fu, X. B.; Zhang, T. M.; Wang, C. Z.; Qian, H. W.; San, Q.

    2011-03-01

    The aim of this article was to study the injury effect of either convergent or parallel argon laser beam on rabbit retina, get the dose-effect relationship for the two types of laser beams, and calculate the damage threshold of argon laser for human retinas. An argon laser therapeutic instrument for ophthalmology was used in this study. A total of 80 rabbit eyes were irradiated for 600 lesions, half of which were treated by convergent laser and the other half were done with parallel laser beam. After irradiation, slit lamp microscope and fundus photography were used to observe the lesions, change and the incidence of injury was processed statistically to get the damage threshold of rabbit retina. Based on results from the experiments on animals and the data from clinical cases of laser treatment, the photocoagulation damage thresholds of human retinas for convergent and parallel argon laser were calculated to be 0.464 and 0.285 mJ respectively. These data provided biological reference for safely operation when employing laser photocoagulation in clinical practice and other fields.

  12. Differential vascular response and relationship to tumor response with photodynamic therapy using WST-09 (TOOKAD)

    NASA Astrophysics Data System (ADS)

    Garbo, Greta M.; Kik, Peter K.; Harrison, Linda T.; Brun, Pierre H.; Blanc, Dominique; Paulin, Pamela S.; Wieman, Thomas J.; Fingar, Victor H.

    2004-06-01

    Bacteriopheophorbide molecules are second-generation photosensitizers with promise for PHotodynamic Therapy applications due largely to their absorption peaks in the near-Infrared region. Palladium bcteriopheophorbide, also called TOOKAD, has been successfully evaluated in several pre-clinical animal models. In this study the effect on tumor and normal vasculature was evaluated using an intravital vascular model on mouse cremaster muscle implanted with the RIF tumor. For tumor response studies, the same RIF tumor was implanted intradermally on the right flank and regression was evaluated for 42 days or until the tumor reached a 12 mm diameter. A light dose 300 J/cm2 were delivered at 763 nm with power density of 100 mW/cm2. Photosensitizer dose was 4 mg/kg body weight. Mice were treated immediately, 10 minutes, 30 minutes, or 24 hours after injection. Only the higher light dose (300 J/cm2) delivered 10 minutes after injection produced a reproducible and complete vascular and tumor response after PDT in these animals. In the cremaster-tumor model, arterioles and venules partially shutdown as early as 40 minutes after the beginning of treatment, while tumor neovasculature was irreversibly closed within 20 minutes of treatment. Tumor response studies demonstrated that the magnitude of vascular stasis correlates with tumor regression studies. Further studies using this photosensitizer are warranted, given its short clearance time and its near-Infrared activation wavelength.

  13. 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

  14. FETAL DEXAMETHASONE EXPOSURE ACCELERATES DEVELOPMENT OF RENAL FUNCTION: RELATIONSHIP TO DOSE, CELL DIFFERENTIATION AND GROWTH INHIBITION

    EPA Science Inventory

    Fetal exposure to high doses of glucocorticoids slows cellular development and impairs organ performance, in association with growth retardation. evertheless, low doses of glucocorticoids may enhance cell differentiation and accelerate specific functions. he current study examine...

  15. Immune response to 1 and 2 dose regimens of Measles vaccine in Pakistani children

    PubMed Central

    Hussain, Hamidah; Akram, Dure Samin; Chandir, Subhash; Khan, Aamir J; Memon, Ashraf; Halsey, Neal A

    2013-01-01

    Measles is a significant problem in Pakistan despite vaccine coverage rates reported at 80%. The purpose of this study was to determine the serologic response in children after one dose of measles vaccine at 9 mo versus two doses at 9 and 15 mo of age. From March through December 2006, children were enrolled from immunization clinics and squatter settlements in Karachi. Blood samples were taken from children in Group A at 9–10 mo of age prior to measles vaccine and 8 to 11 weeks later; from children in Group B at 16–17 mo of age after receiving 2 doses of measles vaccine; and from children in Group C who had received at least one dose of measles vaccine by 5 y of age. After the first dose of measles vaccine, 107/147 (73%) of children in Group A were seropositive, 157/180 (87%) of children in Group B were seropositive after two doses and 126/200 (63%) of children in Group C were seropositive at 5 y of age. The post-vaccination geometric mean antibody concentrations were higher in females than males in groups A (irrespective of pre-vaccination antibody levels) and B. The serologic response to one and two doses of measles vaccine was lower in children in Karachi than has been reported in many other countries. Two doses of vaccine were significantly better than one dose. An in-depth investigation is needed to determine the reason for the lower-than-expected protection rates. Differences in immunogenicity between genders need to be further studied. Recent introduction of supplemental measles vaccine doses should help control measles in Pakistan. PMID:23928952

  16. 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.

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

    2015-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2008-12-01

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

  20. 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...

  1. 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...

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

    PubMed Central

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

    2014-01-01

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

  3. Induction of IgG memory responses with polyvinylpyrrolidone (PVP) is antigen dose dependent

    SciTech Connect

    Lite, H.S.; Braley-Mullen, H.

    1981-03-01

    Irradiated recipients of spleen cells from mice primed with a very low dose (0.0025 ..mu../g) of the thymus-independent (TI) antigen polyvinylpyrrolidone (PVP) produced PVP-specific IgG memory responses after secondary challenge with a T-dependent (TD) form of PVP, PVP-HRBC. The IgG memory responses induced by low doses of PVP were similar in magnitude to those induced by the TD antigen PVP-HRBC. The induction of IgG memory by the TI form of antigen was markedly dependent on the dose of PVP used to prime donor mice. Spleen cells from mice primed with an amount of PVP (0.25 ..mu..g) that induces an optimal primary IgM response did not produce significant IgG antibody after challenge with PVP-HRBC. The inability of higher doses of PVP to induce IgG memory may be due, at least in part, to the fact that such doses of PVP were found to induce tolerance in PVP-specific B cells and could suppress the induction of memory induced by PVP-HRBC. Low doses of PVP did not interfere with the induction of memory by PVP-HRBC. Expression of IgG memory responses in recipients of PVP-HRBC or low-dose PVP-primed cells was found to be T cell dependent. Moreover, only primed T cells could reconstitute the respnse of recipients of primed B cells, suggesting that the ability of PVP to induce IgG memory may be related to its ability to prime T helper cells. Expression of the IgG memory response in recipient mice also required the use of a TD antigen for secondary challenge, i.e., mice challenged with PVP did not develop IgG.

  4. 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

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

    PubMed Central

    2014-01-01

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

  6. Beneficial effects of low dose radiation in response to the oncogenic KRAS induced cellular transformation.

    PubMed

    Kim, Rae-Kwon; Kim, Min-Jung; Seong, Ki Moon; Kaushik, Neha; Suh, Yongjoon; Yoo, Ki-Chun; Cui, Yan-Hong; Jin, Young Woo; Nam, Seon Young; Lee, Su-Jae

    2015-01-01

    Recently low dose irradiation has gained attention in the field of radiotherapy. For lack of understanding of the molecular consequences of low dose irradiation, there is much doubt concerning its risks on human beings. In this article, we report that low dose irradiation is capable of blocking the oncogenic KRAS-induced malignant transformation. To address this hypothesis, we showed that low dose irradiation, at doses of 0.1 Gray (Gy); predominantly provide defensive response against oncogenic KRAS -induced malignant transformation in human cells through the induction of antioxidants without causing cell death and acts as a critical regulator for the attenuation of reactive oxygen species (ROS). Importantly, we elucidated that knockdown of antioxidants significantly enhanced ROS generation, invasive and migratory properties and abnormal acini formation in KRAS transformed normal as well as cancer cells. Taken together, this study demonstrates that low dose irradiation reduces the KRAS induced malignant cellular transformation through diminution of ROS. This interesting phenomenon illuminates the beneficial effects of low dose irradiation, suggesting one of contributory mechanisms for reducing the oncogene induced carcinogenesis that intensify the potential use of low dose irradiation as a standard regimen. PMID:26515758

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

    PubMed

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

    2002-03-01

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

  8. Bayesian model-averaged benchmark dose analysis via reparameterized quantal-response models.

    PubMed

    Fang, Q; Piegorsch, W W; Simmons, S J; Li, X; Chen, C; Wang, Y

    2015-12-01

    An important objective in biomedical and environmental risk assessment is estimation of minimum exposure levels that induce a pre-specified adverse response in a target population. The exposure points in such settings are typically referred to as benchmark doses (BMDs). Parametric Bayesian estimation for finding BMDs has grown in popularity, and a large variety of candidate dose-response models is available for applying these methods. Each model can possess potentially different parametric interpretation(s), however. We present reparameterized dose-response models that allow for explicit use of prior information on the target parameter of interest, the BMD. We also enhance our Bayesian estimation technique for BMD analysis by applying Bayesian model averaging to produce point estimates and (lower) credible bounds, overcoming associated questions of model adequacy when multimodel uncertainty is present. An example from carcinogenicity testing illustrates the calculations. PMID:26102570

  9. Poster — Thur Eve — 27: Flattening Filter Free VMAT Quality Assurance: Dose Rate Considerations for Detector Response

    SciTech Connect

    Viel, Francis; Duzenli, Cheryl; Camborde, Marie-Laure; Strgar, Vincent; Horwood, Ron; Atwal, Parmveer; Gete, Ermias; Karan, Tania

    2014-08-15

    Introduction: Radiation detector responses can be affected by dose rate. Due to higher dose per pulse and wider range of mu rates in FFF beams, detector responses should be characterized prior to implementation of QA protocols for FFF beams. During VMAT delivery, the MU rate may also vary dramatically within a treatment fraction. This study looks at the dose per pulse variation throughout a 3D volume for typical VMAT plans and the response characteristics for a variety of detectors, and makes recommendations on the design of QA protocols for FFF VMAT QA. Materials and Methods: Linac log file data and a simplified dose calculation algorithm are used to calculate dose per pulse for a variety of clinical VMAT plans, on a voxel by voxel basis, as a function of time in a cylindrical phantom. Diode and ion chamber array responses are characterized over the relevant range of dose per pulse and dose rate. Results: Dose per pulse ranges from <0.1 mGy/pulse to 1.5 mGy/pulse in a typical VMAT treatment delivery using the 10XFFF beam. Diode detector arrays demonstrate increased sensitivity to dose (+./− 3%) with increasing dose per pulse over this range. Ion chamber arrays demonstrate decreased sensitivity to dose (+/− 1%) with increasing dose rate over this range. Conclusions: QA protocols should be designed taking into consideration inherent changes in detector sensitivity with dose rate. Neglecting to account for changes in detector response with dose per pulse can lead to skewed QA results.

  10. Mechanisms underlying cellular responses of cells from haemopoietic tissue to low dose/low LET radiation

    SciTech Connect

    Munira A Kadhim

    2010-03-05

    To accurately define the risks associated with human exposure to relevant environmental doses of low LET ionizing radiation, it is necessary to completely understand the biological effects at very low doses (i.e., less than 0.1 Gy), including the lowest possible dose, that of a single electron track traversal. At such low doses, a range of studies have shown responses in biological systems which are not related to the direct interaction of radiation tracks with DNA. The role of these “non-targeted” responses in critical tissues is poorly understood and little is known regarding the underlying mechanisms. Although critical for dosimetry and risk assessment, the role of individual genetic susceptibility in radiation risk is not satisfactorily defined at present. The aim of the proposed grant is to critically evaluate radiation-induced genomic instability and bystander responses in key stem cell populations from haemopoietic tissue. Using stem cells from two mouse strains (CBA/H and C57BL/6J) known to differ in their susceptibility to radiation effects, we plan to carefully dissect the role of genetic predisposition on two non-targeted radiation responses in these models; the bystander effect and genomic instability, which we believe are closely related. We will specifically focus on the effects of low doses of low LET radiation, down to doses approaching a single electron traversal. Using conventional X-ray and γ-ray sources, novel dish separation and targeted irradiation approaches, we will be able to assess the role of genetic variation under various bystander conditions at doses down to a few electron tracks. Irradiations will be carried out using facilities in routine operation for bystander targeted studies. Mechanistic studies of instability and the bystander response in different cell lineages will focus initially on the role of cytokines which have been shown to be involved in bystander signaling and the initiation of instability. These studies also aim

  11. A comparison of linaclotide and lubiprostone dosing regimens on ion transport responses in human colonic mucosa.

    PubMed

    Kang, Sang Bum; Marchelletta, Ronald R; Penrose, Harrison; Docherty, Michael J; McCole, Declan F

    2015-03-01

    Linaclotide, a synthetic guanylyl cyclase C (GC-C) agonist, and the prostone analog, Lubiprostone, are approved to manage chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. Lubiprostone also protects intestinal mucosal barrier function in ischemia. GC-C signaling regulates local fluid balance and other components of intestinal mucosal homeostasis including epithelial barrier function. The aim of this study was to compare if select dosing regimens differentially affect linaclotide and lubiprostone modulation of ion transport and barrier properties of normal human colonic mucosa. Normal sigmoid colon biopsies from healthy subjects were mounted in Ussing chambers. Tissues were treated with linaclotide, lubiprostone, or vehicle to determine effects on short-circuit current (I sc). Subsequent I sc responses to the cAMP agonist, forskolin, and the calcium agonist, carbachol, were also measured to assess if either drug caused desensitization. Barrier properties were assessed by measuring transepithelial electrical resistance. I sc responses to linaclotide and lubiprostone were significantly higher than vehicle control when administered bilaterally or to the mucosal side only. Single versus cumulative concentrations of linaclotide showed differences in efficacy while cumulative but not single dosing caused desensitization to forskolin. Lubiprostone reduced forskolin responses under all conditions. Linaclotide and lubiprostone exerted a positive effect on TER that was dependent on the dosing regimen. Linaclotide and lubiprostone increase ion transport responses across normal human colon but linaclotide displays increased sensitivity to the dosing regimen used. These findings may have implications for dosing protocols of these agents in patients with constipation. PMID:26038704

  12. A comparison of linaclotide and lubiprostone dosing regimens on ion transport responses in human colonic mucosa

    PubMed Central

    Kang, Sang Bum; Marchelletta, Ronald R; Penrose, Harrison; Docherty, Michael J; McCole, Declan F

    2015-01-01

    Linaclotide, a synthetic guanylyl cyclase C (GC-C) agonist, and the prostone analog, Lubiprostone, are approved to manage chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. Lubiprostone also protects intestinal mucosal barrier function in ischemia. GC-C signaling regulates local fluid balance and other components of intestinal mucosal homeostasis including epithelial barrier function. The aim of this study was to compare if select dosing regimens differentially affect linaclotide and lubiprostone modulation of ion transport and barrier properties of normal human colonic mucosa. Normal sigmoid colon biopsies from healthy subjects were mounted in Ussing chambers. Tissues were treated with linaclotide, lubiprostone, or vehicle to determine effects on short-circuit current (Isc). Subsequent Isc responses to the cAMP agonist, forskolin, and the calcium agonist, carbachol, were also measured to assess if either drug caused desensitization. Barrier properties were assessed by measuring transepithelial electrical resistance. Isc responses to linaclotide and lubiprostone were significantly higher than vehicle control when administered bilaterally or to the mucosal side only. Single versus cumulative concentrations of linaclotide showed differences in efficacy while cumulative but not single dosing caused desensitization to forskolin. Lubiprostone reduced forskolin responses under all conditions. Linaclotide and lubiprostone exerted a positive effect on TER that was dependent on the dosing regimen. Linaclotide and lubiprostone increase ion transport responses across normal human colon but linaclotide displays increased sensitivity to the dosing regimen used. These findings may have implications for dosing protocols of these agents in patients with constipation. PMID:26038704

  13. Infectious Dose Dictates the Host Response during Staphylococcus aureus Orthopedic-Implant Biofilm Infection.

    PubMed

    Vidlak, Debbie; Kielian, Tammy

    2016-07-01

    Staphylococcus aureus is a leading cause of prosthetic joint infections (PJIs) that are typified by biofilm formation. Given the diversity of S. aureus strains and their propensity to cause community- or hospital-acquired infections, we investigated whether the immune response and biofilm growth during PJI were conserved among distinct S. aureus clinical isolates. Three S. aureus strains representing USA200 (UAMS-1), USA300 (LAC), and USA400 (MW2) lineages were equally effective at biofilm formation in a mouse model of PJI and elicited similar leukocyte infiltrates and cytokine/chemokine profiles. Another factor that may influence the course of PJI is infectious dose. In particular, higher bacterial inocula could accelerate biofilm formation and alter the immune response, making it difficult to discern underlying pathophysiological mechanisms. To address this issue, we compared the effects of two bacterial doses (10(3) or 10(5) CFU) on inflammatory responses in interleukin-12p40 (IL-12p40) knockout mice that were previously shown to have reduced myeloid-derived suppressor cell recruitment concomitant with bacterial clearance after low-dose challenge (10(3) CFU). Increasing the infectious dose of LAC to 10(5) CFU negated these differences in IL-12p40 knockout animals, demonstrating the importance of bacterial inoculum on infection outcome. Collectively, these observations highlight the importance of considering infectious dose when assessing immune responsiveness, whereas biofilm formation during PJI is conserved among clinical isolates commonly used in mouse S. aureus infection models. PMID:27091926

  14. Biological Dose Response to PM2.5: Effect of Particle Extraction Method on Platelet and Lung Responses

    PubMed Central

    Van Winkle, Laura S.; Bein, Keith; Anderson, Donald; Pinkerton, Kent E.; Tablin, Fern; Wilson, Dennis; Wexler, Anthony S.

    2015-01-01

    Particulate matter (PM) exposure contributes to respiratory diseases and cardiopulmonary mortality. PM toxicity is related to sources and composition, such as abundance of polycyclic aromatic hydrocarbons (PAHs). We exposed adult male BALB/c mice, via oropharyngeal aspiration, to a range of doses of PM2.5 collected during the winter in downtown Sacramento near a major freeway interchange (SacPM). Two preparation methods (spin-down and multi-solvent extraction) were tested to remove particles from collection filters. Three doses were analyzed 24 h after treatment for (1) leukocytes and total protein in bronchoalveolar lavage fluid (BALF), (2) airway-specific and whole lobe expression of PAH-sensitive genes (CYP1B1 and CYP1A1) and IL-1 b, (3) lung histology, and (4) platelet function. Both extraction methods stimulated biological responses, but the spin-down method was more robust at producing IL-1 b and CYP1B1 gene responses and the multi-solvent extraction induced whole lung CYP1A1. Neutrophils in the BALF were increased 5- to 10-fold at the mid and high dose for both preparations. Histopathology scores indicated dose-dependent responses and increased pathology associated with spin-down-derived PM exposure. In microdissected airways, spin-down PM increased CYP1B1 gene expression significantly, but multi-solvent extracted PM did not. Platelet responses to the physiological agonist thrombin were approximately twice as potent in the spin-down preparation as in the multi-solvent extract. We conclude (1) the method of filter extraction can influence the degree of biological response, (2) for SacPM the minimal effective dose is 27.5–50 µg based on neutrophil recruitment, and (3) P450s are upregulated differently in airways and lung parenchyma in response to PAH-containing PM. PMID:25389146

  15. Biological dose response to PM2.5: effect of particle extraction method on platelet and lung responses.

    PubMed

    Van Winkle, Laura S; Bein, Keith; Anderson, Donald; Pinkerton, Kent E; Tablin, Fern; Wilson, Dennis; Wexler, Anthony S

    2015-02-01

    Particulate matter (PM) exposure contributes to respiratory diseases and cardiopulmonary mortality. PM toxicity is related to sources and composition, such as abundance of polycyclic aromatic hydrocarbons (PAHs). We exposed adult male BALB/c mice, via oropharyngeal aspiration, to a range of doses of PM2.5 collected during the winter in downtown Sacramento near a major freeway interchange (SacPM). Two preparation methods (spin-down and multi-solvent extraction) were tested to remove particles from collection filters. Three doses were analyzed 24 h after treatment for (1) leukocytes and total protein in bronchoalveolar lavage fluid (BALF), (2) airway-specific and whole lobe expression of PAH-sensitive genes (CYP1B1 and CYP1A1) and IL-1 b, (3) lung histology, and (4) platelet function. Both extraction methods stimulated biological responses, but the spin-down method was more robust at producing IL-1 b and CYP1B1 gene responses and the multi-solvent extraction induced whole lung CYP1A1. Neutrophils in the BALF were increased 5- to 10-fold at the mid and high dose for both preparations. Histopathology scores indicated dose-dependent responses and increased pathology associated with spin-down-derived PM exposure. In microdissected airways, spin-down PM increased CYP1B1 gene expression significantly, but multi-solvent extracted PM did not. Platelet responses to the physiological agonist thrombin were approximately twice as potent in the spin-down preparation as in the multi-solvent extract. We conclude (1) the method of filter extraction can influence the degree of biological response, (2) for SacPM the minimal effective dose is 27.5-50 µg based on neutrophil recruitment, and (3) P450s are upregulated differently in airways and lung parenchyma in response to PAH-containing PM. PMID:25389146

  16. Temporal processes that contribute to nonlinearity in vegetation responses to ozone exposure and dose

    NASA Astrophysics Data System (ADS)

    Heath, Robert L.; Lefohn, Allen S.; Musselman, Robert C.

    Ozone interacts with plant tissue through distinct temporal processes. Sequentially, plants are exposed to ambient O 3 that (1) moves through the leaf boundary layer, (2) is taken up into plant tissue primarily through stomata, and (3) undergoes chemical interaction within plant tissue, first by initiating alterations and then as part of plant detoxification and repair. In this paper, we discuss the linkage of the temporal variability of apoplastic ascorbate with the diurnal variability of defense mechanisms in plants and compare this variability with daily maximum O 3 concentration and diurnal uptake and entry of O 3 into the plant through stomata. We describe the quantitative evidence on temporal variability in concentration and uptake and find that the time incidence for maximum defense does not necessarily match diurnal patterns for maximum O 3 concentration or maximum uptake. We suggest that the observed out-of-phase association of the diurnal patterns for the above three processes produces a nonlinear relationship that results in a greater response from the higher hourly average O 3 concentrations than from the lower or mid-level values. The fact that these out-of-phase processes affect the relationship between O 3 exposure/dose and vegetation effects ultimately impact the ability of flux-based indices to predict vegetation effects accurately for purposes of standard setting and critical levels. Based on the quantitative aspect of temporal variability identified in this paper, we suggest that the inclusion of a diurnal pattern for detoxification in effective flux-based models would improve the predictive characteristics of the models. While much of the current information has been obtained using high O 3 exposures, future research results derived from laboratory biochemical experiments that use short but elevated O 3 exposures should be combined with experimental results that use ambient-type exposures over longer periods of time. It is anticipated that

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

    PubMed

    Nakashima, Eiji

    2015-07-01

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

  18. Cellular response to low dose radiation: Role of phosphatidylinositol-3 kinase like kinases

    SciTech Connect

    Balajee, A.S.; Meador, J.A.; Su, Y.

    2011-03-24

    It is increasingly realized that human exposure either to an acute low dose or multiple chronic low doses of low LET radiation has the potential to cause different types of cancer. Therefore, the central theme of research for DOE and NASA is focused on understanding the molecular mechanisms and pathways responsible for the cellular response to low dose radiation which would not only improve the accuracy of estimating health risks but also help in the development of predictive assays for low dose radiation risks associated with tissue degeneration and cancer. The working hypothesis for this proposal is that the cellular mechanisms in terms of DNA damage signaling, repair and cell cycle checkpoint regulation are different for low and high doses of low LET radiation and that the mode of action of phosphatidylinositol-3 kinase like kinases (PIKK: ATM, ATR and DNA-PK) determines the dose dependent cellular responses. The hypothesis will be tested at two levels: (I) Evaluation of the role of ATM, ATR and DNA-PK in cellular response to low and high doses of low LET radiation in simple in vitro human cell systems and (II) Determination of radiation responses in complex cell microenvironments such as human EpiDerm tissue constructs. Cellular responses to low and high doses of low LET radiation will be assessed from the view points of DNA damage signaling, DNA double strand break repair and cell cycle checkpoint regulation by analyzing the activities (i.e. post-translational modifications and kinetics of protein-protein interactions) of the key target proteins for PI-3 kinase like kinases both at the intra-cellular and molecular levels. The proteins chosen for this proposal are placed under three categories: (I) sensors/initiators include ATM ser1981, ATR, 53BP1, gamma-H2AX, MDC1, MRE11, Rad50 and Nbs1; (II) signal transducers include Chk1, Chk2, FANCD2 and SMC1; and (III) effectors include p53, CDC25A and CDC25C. The primary goal of this proposal is to elucidate the

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

    PubMed

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

    2014-01-16

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

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

    PubMed Central

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

    2014-01-01

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

  1. 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

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

    PubMed

    Holland-Letz, Tim; Kopp-Schneider, Annette

    2015-11-01

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

  3. Concentration-response relationship for fluvoxamine using remission as an endpoint: a receiver operating characteristics curve analysis in major depression.

    PubMed

    Suzuki, Yutaro; Fukui, Naoki; Sawamura, Kazushi; Sugai, Takuro; Watanabe, Junzo; Ono, Shin; Inoue, Yoshimasa; Ozdemir, Vural; Someya, Toshiyuki

    2008-06-01

    Therapeutic drug monitoring studies of selective serotonin reuptake inhibitor (SSRI) antidepressants thus far failed to identify a clear concentration-response relationship in major depression. Majority of the previous studies defined clinical response as 50% or greater reduction from baseline in depression rating scale scores. Because many patients who meet these criteria still present symptoms associated with functional impairment, there is a need to consider "remission" as an alternative end point in concentration-response analyses of SSRIs. The present 12-week prospective study investigated the relationship between fluvoxamine (an SSRI) plasma concentration and remission in outpatients with depression. We used a flexible dose titration study designed to mimic clinical practice within the therapeutic dose range of fluvoxamine (25-200 mg/d). Receiver operating characteristics (ROC) curve was computed to determine the optimal fluvoxamine plasma concentration for remission using 269 concentration data obtained from 80 patients. Analysis of the ROC curve from the entire study sample did not reveal a fluvoxamine concentration significantly predicting remission. By contrast, ROC analysis specifically in patients with moderate to severe depression (N = 51; baseline 17-item Hamilton Rating Scale for Depression score > or = 20) found a fluvoxamine concentration of 61.4 ng/mL as a significant predictor of remission. In conclusion, therapeutic drug monitoring may be useful for rational titration and individualization of fluvoxamine dose and predicting remission in patients with moderate to severe depression, who may presumably display lesser placebo component in pharmacodynamic response. PMID:18480690

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

    PubMed

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

    2016-05-01

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

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

    PubMed

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

    2016-04-01

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

  6. Dose-Effect Relationships for Adverse Events After Cranial Radiation Therapy in Long-term Childhood Cancer Survivors

    SciTech Connect

    Dijk, Irma W.E.M. van; Cardous-Ubbink, Mathilde C.; Pal, Helena J.H. van der; Oldenburger, Foppe; Os, Rob M. van; Ronckers, Cécile M.; Schouten–van Meeteren, Antoinette Y.N.; Kremer, Leontien C.M.

    2013-03-01

    Purpose: To evaluate the prevalence and severity of clinical adverse events (AEs) and treatment-related risk factors in childhood cancer survivors treated with cranial radiation therapy (CRT), with the aim of assessing dose-effect relationships. Methods and Materials: The retrospective study cohort consisted of 1362 Dutch childhood cancer survivors, of whom 285 were treated with CRT delivered as brain irradiation (BI), as part of craniospinal irradiation (CSI), and as total body irradiation (TBI). Individual CRT doses were converted into the equivalent dose in 2-Gy fractions (EQD{sub 2}). Survivors had received their diagnoses between 1966 and 1996 and survived at least 5 years after diagnosis. A complete inventory of Common Terminology Criteria for Adverse Events grade 3.0 AEs was available from our hospital-based late-effect follow-up program. We used multivariable logistic and Cox regression analyses to examine the EQD{sub 2} in relation to the prevalence and severity of AEs, correcting for sex, age at diagnosis, follow-up time, and the treatment-related risk factors surgery and chemotherapy. Results: There was a high prevalence of AEs in the CRT group; over 80% of survivors had more than 1 AE, and almost half had at least 5 AEs, both representing significant increases in number of AEs compared with survivors not treated with CRT. Additionally, the proportion of severe, life-threatening, or disabling AEs was significantly higher in the CRT group. The most frequent AEs were alopecia and cognitive, endocrine, metabolic, and neurologic events. Using the EQD{sub 2}, we found significant dose-effect relationships for these and other AEs. Conclusion: Our results confirm that CRT increases the prevalence and severity of AEs in childhood cancer survivors. Furthermore, analyzing dose-effect relationships with the cumulative EQD{sub 2} instead of total physical dose connects the knowledge from radiation therapy and radiobiology with the clinical experience.

  7. Response of lymphoid organs to low dose rate Cf-252, Cs-137 and acute Co-60

    SciTech Connect

    Feola, J.; Maruyama, Y.; Magura, C.; Hwang, H.N.

    1986-01-01

    RBE of low dose rate (LDR) /sup 252/Cf radiation was studied for thymus using weight loss compared to unirradiated controls. These were compared against LDR /sup 137/Cs and acute /sup 60/Co effects. For thymus, biexponential dose response curves were noted for acute /sup 60/Co and LDR /sup 137/Cs irradiations. No dose rate effect was noted with /sup 137/Cs. D/sub 37/ for the first component D/sub 1/ was 109 cGy and for the second D/sub 2/ was 624 cGy for /sup 60/Co. Relative biological effectiveness (RBE) is a complex endpoint and was different for the low dose (sensitive) and high dose (resistant) responses and for /sup 252/Cf. RBE/sub n/ of the sensitive portion was 1.7 and for overall was 4.0. Spleen response was also determined for the 3 radiations. Biexponential dose-response curves were also observed for resting spleen to acute /sup 60/Co and LDR /sup 137/Cs radiation. D/sub 1/ = 285 cGy and D/sub 2/ = 1538 cGy for acute /sup 60/Co; D/sub 1/ = 205 cGy for /sup 137/Cs and indicated a dose rate effect = 1.04 for /sup 137/Cs. The LDR /sup 137/Cs was 1.3x more effective than acute /sup 60/Co for the sensitive response; it was 1.9 x greater for the resistant response. However, the response to /sup 252/Cf vs. /sup 137/Cs for the spleen indicated that there was a greater sensitivity to dose rate than to LET. RBE/sub n/ for /sup 252/Cf vs. /sup 137/Cs was 1.0. Stimulation of spleen growth after injection of Corynebacterium parvum allowed study of radiation effects of proliferating spleen cells at day 10. Acute /sup 60/Co and LDR /sup 137/Cs ..gamma..-rays had reduced effects compared to LDR /sup 252/Cf radiation and RBE was 4.0 vs. LDR /sup 137/Cs. RBE in lymphoid organs thus depended on organ, on assay and on resting/proliferating status.

  8. A Response Surface Model Exploration of Dosing Strategies in Gastrointestinal Endoscopies Using Midazolam and Opioids.

    PubMed

    Liou, Jing-Yang; Ting, Chien-Kun; Hou, Ming-Chih; Tsou, Mei-Yung

    2016-06-01

    Classical midazolam-opioid combination for gastrointestinal endoscopy sedation has been adopted for decades. Dosing regimens have been studied but most require fixed dosing intervals. We intend to use a sophisticated pharmacodynamic tool, response surface model (RSM), to simulate sedation using different regimens. RSM can predict patient's response during different phases of the examination and predict patient's wake-up time with precision and without the need for fixed dosing intervals. We believe it will aid physicians in guiding their dosing strategy and timing.The study is divided into 2 parts. The first part is the full Greco RSMs development for 3 distinct phases: esophagogastroduodenoscopy (EGD), colonoscopy, and intersession (the time lapse between procedures). Observer's Assessment of Alertness Score (OAA/S) is used to assess patient response. The second part simulates 6 regimens with different characteristics using the RSMs: midazolam only, balanced midazolam and opioids, high-dose opioids and midazolam, low-dose midazolam with high-dose opioids, high-dose midazolam and low-dose opioids, and finally midazolam with continuous opioid infusion. Loss of response at 95% probability for adequate anesthesia during examination and return of consciousness at 50% probability during intersession was selected for simulation purposes.The average age of the patient population is 49.3 years. Mean BMI is 21.9 ± 2.3 kg/m. About 56.7% were females and none received prior abdominal surgery. The cecal intubation rate was 100%. Only 1 patient (3%) developed temporary hypoxemia, which was promptly managed with simple measures. The RSMs for each phase showed significant synergy between midazolam and alfentanil. The balanced midazolam and alfentanil combination provided adequate anesthesia and most rapid return of consciousness. The awakening time from the final drug bolus was 7.4 minutes during EGD and colonoscopy stimulation, and 9.1 minutes during EGD simulation

  9. A Response Surface Model Exploration of Dosing Strategies in Gastrointestinal Endoscopies Using Midazolam and Opioids

    PubMed Central

    Liou, Jing-Yang; Ting, Chien-Kun; Hou, Ming-Chih; Tsou, Mei-Yung

    2016-01-01

    Abstract Classical midazolam–opioid combination for gastrointestinal endoscopy sedation has been adopted for decades. Dosing regimens have been studied but most require fixed dosing intervals. We intend to use a sophisticated pharmacodynamic tool, response surface model (RSM), to simulate sedation using different regimens. RSM can predict patient's response during different phases of the examination and predict patient's wake-up time with precision and without the need for fixed dosing intervals. We believe it will aid physicians in guiding their dosing strategy and timing. The study is divided into 2 parts. The first part is the full Greco RSMs development for 3 distinct phases: esophagogastroduodenoscopy (EGD), colonoscopy, and intersession (the time lapse between procedures). Observer's Assessment of Alertness Score (OAA/S) is used to assess patient response. The second part simulates 6 regimens with different characteristics using the RSMs: midazolam only, balanced midazolam and opioids, high-dose opioids and midazolam, low-dose midazolam with high-dose opioids, high-dose midazolam and low-dose opioids, and finally midazolam with continuous opioid infusion. Loss of response at 95% probability for adequate anesthesia during examination and return of consciousness at 50% probability during intersession was selected for simulation purposes. The average age of the patient population is 49.3 years. Mean BMI is 21.9 ± 2.3 kg/m2. About 56.7% were females and none received prior abdominal surgery. The cecal intubation rate was 100%. Only 1 patient (3%) developed temporary hypoxemia, which was promptly managed with simple measures. The RSMs for each phase showed significant synergy between midazolam and alfentanil. The balanced midazolam and alfentanil combination provided adequate anesthesia and most rapid return of consciousness. The awakening time from the final drug bolus was 7.4 minutes during EGD and colonoscopy stimulation, and 9.1 minutes during EGD

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

    PubMed Central

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

    1987-01-01

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

  11. Radiobiological Response of Cervical Cancer Cell Line in Low Dose Region: Evidence of Low Dose Hypersensitivity (HRS) and Induced Radioresistance (IRR)

    PubMed Central

    Singh, Rabiraja; George, Daicy; Vijaykumar, T.S.; John, Subhashini

    2015-01-01

    Background Purpose of the present study was to examine the response of cervical cancer cell line (HeLa cell line) to low dose radiation using clonogenic assay and mathematical modeling of the low dose response by Joiner’s induced repair model. Materials and Methods Survival of HeLa cells following exposure to single and fractionated low doses of γ (gamma)-ray, 6 MV, and 15 MV photon was measured by clonogenic assay. Results HeLa cell line demonstrated marked low dose response consisting of an area of HRS and IRR in the dose region of <1 Gy. The two gradients of the low dose region (αs and αr) were distinctly different with a transition dose (Dc) of 0.28-0.40 cGy. Conclusion HeLa cell line demonstrates marked HRS and IRR with distinct transition dose. This may form the biological basis of the clinical study to investigate the chemo potentiating effect of low dose radiation in cervical cancer. PMID:26266200

  12. The high dose response and functional capability of the DT-702/Pd lithium fluoride thermoluminescent dosimeter.

    PubMed

    Lawlor, Tyler M; Talmadge, Molly D; Murray, Mark M; Nelson, Martin E; Mueller, Andrew C; Romanyukha, Alexander A; Fairchild, Gregory R; Grypp, Matthew D; Williams, Anthony S

    2015-05-01

    The United States Navy monitors the dose its radiation workers receive using the DT-702/PD thermoluminescent dosimeter, which consists of the Harshaw 8840 holder and the four-element Harshaw 8841 card. There were two main objectives of this research. In the first objective, the dosimeters were exposed to 100 Gy using electron and x-ray beams and found to respond approximately 30-40% lower than the delivered dose. No significant effect on the under-response was found when dose rate, radiation type, dosimeter position on the phantom, and dosimeter material were varied or when the card was irradiated while enclosed in its holder. Since the current naval policy is to remove from occupational use any thermoluminescent dosimeter with an accumulated deep dose equivalent of 0.05 Sv or greater, the functionality of the dosimeter was also investigated at deep dose equivalents of 0.05, 0.15, and 0.25 Sv using 60Co and 137Cs sources as the second main objective. All dosimeters were annealed following exposure and then exposed to 5.0 mSv from a 90Sr source. In all cases, the dosimeters responded within 3% of the delivered dose, indicating that the dosimeters remained functional as defined by naval dosimetry requirements. However, the anneal time required to clear the thermoluminescent dosimeter's reading was found to increase approximately as the cube root with the delivered dose. PMID:25811149

  13. Influence of Dose Rate on the Cellular Response to Low- and High-LET Radiations

    PubMed Central

    Wozny, Anne-Sophie; Alphonse, Gersende; Battiston-Montagne, Priscillia; Simonet, Stéphanie; Poncet, Delphine; Testa, Etienne; Guy, Jean-Baptiste; Rancoule, Chloé; Magné, Nicolas; Beuve, Michael; Rodriguez-Lafrasse, Claire

    2016-01-01

    Nowadays, head and neck squamous cell carcinoma (HNSCC) treatment failure is mostly explained by locoregional progression or intrinsic radioresistance. Radiotherapy (RT) has recently evolved with the emergence of heavy ion radiations or new fractionation schemes of photon therapy, which modify the dose rate of treatment delivery. The aim of the present study was then to evaluate the in vitro influence of a dose rate variation during conventional RT or carbon ion hadrontherapy treatment in order to improve the therapeutic care of patient. In this regard, two HNSCC cell lines were irradiated with photons or 72 MeV/n carbon ions at a dose rate of 0.5, 2, or 10 Gy/min. For both radiosensitive and radioresistant cells, the change in dose rate significantly affected cell survival in response to photon exposure. This variation of radiosensitivity was associated with the number of initial and residual DNA double-strand breaks (DSBs). By contrast, the dose rate change did not affect neither cell survival nor the residual DNA DSBs after carbon ion irradiation. As a result, the relative biological efficiency at 10% survival increased when the dose rate decreased. In conclusion, in the RT treatment of HNSCC, it is advised to remain very careful when modifying the classical schemes toward altered fractionation. At the opposite, as the dose rate does not seem to have any effects after carbon ion exposure, there is less need to adapt hadrontherapy treatment planning during active system irradiation. PMID:27014633

  14. Observation of a Dose-Control Relationship for Lung and Liver Tumors After Stereotactic Body Radiation Therapy

    SciTech Connect

    McCammon, Robert Schefter, Tracey E.; Gaspar, Laurie E.; Zaemisch, Rebekah; Gravdahl, Daniel; Kavanagh, Brian

    2009-01-01

    Purpose: To determine prognostic factors for local control of primary or metastatic tumors within the lung or liver treated with stereotactic body radiation therapy (SBRT) within a single institution. Methods and Materials: The records of 141 consecutive patients with 246 lesions treated with three-fraction SBRT from Oct 1999 through Aug 2005 were reviewed. Local control was assessed radiographically. Univariate and multivariate analyses were performed to evaluate the influence of the following factors on local control: total dose, expressed as either nominal prescription dose or equivalent uniform dose (EUD); gross tumor volume; primary site; treatment site (lung vs. other); histologic characteristics (adenocarcinoma vs. other); gender; age; and primary vs. metastatic tumor. Results: On univariate analysis, increased dose (either nominal or EUD) and smaller gross tumor volume were significant predictors of higher local control. Lesions treated to a nominal dose of 54 Gy or greater had a 3-year actuarial local control rate of 89.3% compared with 59.0% and 8.1% for those treated to 36-53.9 Gy and less than 36 Gy. On multivariate analysis, only increased nominal dose and EUD retained statistical significance. Treatment was well tolerated; 5.7% of patients experienced Grade 3 or higher toxicity. Conclusions: This large single-institution series suggests a dose-control relationship within the range of SBRT doses applied. Excellent local control rates are achieved with a nominal dose of 54 Gy or greater, corresponding to an EUD greater than 65.3 Gy. These results support the use of aggressive SBRT regimens when durable tumor control is the primary objective.

  15. 'Omics analysis of low dose acetaminophen intake demonstrates novel response pathways in humans

    SciTech Connect

    Jetten, Marlon J.A.; Gaj, Stan; Ruiz-Aracama, Ainhoa; Kok, Theo M. de; Delft, Joost H.M. van; Lommen, Arjen; Someren, Eugene P. van; Jennen, Danyel G.J.; Claessen, Sandra M.; Peijnenburg, Ad A.C.M.; Stierum, Rob H.; Kleinjans, Jos C.S.

    2012-03-15

    Acetaminophen is the primary cause of acute liver toxicity in Europe/USA, which led the FDA to reconsider recommendations concerning safe acetaminophen dosage/use. Unfortunately, the current tests for liver toxicity are no ideal predictive markers for liver injury, i.e. they only measure acetaminophen exposure after profound liver toxicity has already occurred. Furthermore, these tests do not provide mechanistic information. Here, 'omics techniques (global analysis of metabolomic/gene-expression responses) may provide additional insight. To better understand acetaminophen-induced responses at low doses, we evaluated the effects of (sub-)therapeutic acetaminophen doses on metabolite formation and global gene-expression changes (including, for the first time, full-genome human miRNA expression changes) in blood/urine samples from healthy human volunteers. Many known and several new acetaminophen-metabolites were detected, in particular in relation to hepatotoxicity-linked, oxidative metabolism of acetaminophen. Transcriptomic changes indicated immune-modulating effects (2 g dose) and oxidative stress responses (4 g dose). For the first time, effects of acetaminophen on full-genome human miRNA expression have been considered and confirmed the findings on mRNA level. 'Omics techniques outperformed clinical chemistry tests and revealed novel response pathways to acetaminophen in humans. Although no definitive conclusion about potential immunotoxic effects of acetaminophen can be drawn from this study, there are clear indications that the immune system is triggered even after intake of low doses of acetaminophen. Also, oxidative stress-related gene responses, similar to those seen after high dose acetaminophen exposure, suggest the occurrence of possible pre-toxic effects of therapeutic acetaminophen doses. Possibly, these effects are related to dose-dependent increases in levels of hepatotoxicity-related metabolites. -- Highlights: ► 'Omics techniques outperformed

  16. 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

  17. Acute small bowel toxicity and preoperative chemoradiotherapy for rectal cancer: Investigating dose-volume relationships and role for inverse planning

    SciTech Connect

    Tho, Lye Mun . E-mail: l.tho@beatson.gla.ac.uk; Glegg, Martin; Paterson, Jennifer; Yap, Christina; MacLeod, Alice; McCabe, Marie; McDonald, Alexander C.

    2006-10-01

    Purpose: The relationship between volume of irradiated small bowel (VSB) and acute toxicity in rectal cancer radiotherapy is poorly quantified, particularly in patients receiving concurrent preoperative chemoradiotherapy. Using treatment planning data, we studied a series of such patients. Methods and Materials: Details of 41 patients with locally advanced rectal cancer were reviewed. All received 45 Gy in 25 fractions over 5 weeks, 3-4 fields three-dimensional conformal radiotherapy with daily 5-fluorouracil and folinic acid during Weeks 1 and 5. Toxicity was assessed prospectively in a weekly clinic. Using computed tomography planning software, the VSB was determined at 5 Gy dose intervals (V{sub 5}, V{sub 1}, etc.). Eight patients with maximal VSB had dosimetry and radiobiological modeling outcomes compared between inverse and conformal three-dimensional planning. Results: VSB correlated strongly with diarrheal severity at every dose level (p < 0.03), with strongest correlation at lowest doses. Median VSB differed significantly between patients experiencing Grade 0-1 and Grade 2-4 diarrhea (p {<=} 0.05). No correlation was found with anorexia, nausea, vomiting, abdominal cramps, age, body mass index, sex, tumor position, or number of fields. Analysis of 8 patients showed that inverse planning reduced median dose to small bowel by 5.1 Gy (p = 0.008) and calculated late normal tissue complication probability (NTCP) by 67% (p = 0.016). We constructed a model using mathematical analysis to predict for acute diarrhea occurring at V{sub 5} and V{sub 15}. Conclusions: A strong dose-volume relationship exists between VSB and acute diarrhea at all dose levels during preoperative chemoradiotherapy. Our constructed model may be useful in predicting toxicity, and this has been derived without the confounding influence of surgical excision on bowel function. Inverse planning can reduce calculated dose to small bowel and late NTCP, and its clinical role warrants further

  18. Response of osteosarcoma to preoperative intravenous high-dose methotrexate chemotherapy: CT evaluation

    SciTech Connect

    Mail, J.T.; Cohen, M.D.; Mirkin, L.D.; Provisor, A.J.

    1985-01-01

    The histologic response of an osteosarcoma to preamputation high-dose methotrexate therapy can be used to determine the optimum maintenance chemotherapy regimen to be administered after amputation. This study evaluates computed tomography (CT) as a method of assessing the response of the tumor to the methotrexate therapy. Nine patients with nonmetastatic osteosarcoma of an extremity had a CT scan of the tumor at initial presentation. This was compared with a second CT scan after four courses of high-dose intravenous methotrexate. Each set of scans was evaluated for changes in bony destruction, soft-tissue mass, pattern of calcification, and extent of tumor involvement of the marrow cavity. These findings were correlated with the histologic response of the tumor as measured by the degree of tumor necrosis. The changes seen on CT correlated well with the degree of the histologic response in seven of the nine patients.

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

    PubMed

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

    2012-09-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2012-09-01

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

  1. Cotton dust and endotoxin exposure-response relationships in cotton textile workers

    SciTech Connect

    Kennedy, S.M.; Christiani, D.C.; Eisen, E.A.; Wegman, D.H.; Greaves, I.A.; Olenchock, S.A.; Ye, T.T.; Lu, P.L.

    1987-01-01

    Endotoxin exposure has been implicated in the etiology of lung disease in cotton workers. We investigated this potential relationship in 443 cotton workers from 2 factories in Shanghai and 439 control subjects from a nearby silk mill. A respiratory questionnaire was administered and pre- and postshift forced expiratory volume (FVC) and flow in one second (FEV1) were determined for each worker. Multiple area air samples were analyzed for total elutriated dust concentration (range: 0.15 to 2.5 mg/m3) and endotoxin (range: 0.002 to 0.55 microgram U.S. Reference Endotoxin/m3). The cotton worker population was stratified by current and cumulative dust or endotoxin exposure. Groups were compared for FEV1, FVC, FEV1/FVC%, % change in FEV1 over the shift (delta FEV1%), and prevalences of chronic bronchitis and byssinosis, and linear and logistic regression models were constructed. No dose-response relationships were demonstrated comparing dust concentration to any pulmonary function or symptom variable. A dose-response trend was seen with the current endotoxin level and FEV1, delta FEV1%, and the prevalence of byssinosis and chronic bronchitis, except for the highest exposure level group in which a reversal of the trend was seen. The regression coefficients for current endotoxin exposure were significant (p less than 0.05) in the models for FEV1 and chronic bronchitis but not in the models for delta FEV1% (i.e., acute change in FEV1) or byssinosis prevalence. The coefficient for dust level was never significant in the models.

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

    PubMed Central

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

    2003-01-01

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

  3. 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...

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

    EPA Science Inventory

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

  5. 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...

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  7. 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...

  8. RISK ASSESSMENT FOR CRYPTOSPORIDIUM: A HIERARCHICAL BAYESIAN ANALYSIS OF HUMAN DOSE-RESPONSE DATA. (R829180)

    EPA Science Inventory

    Three dose–response studies were conducted with healthy volunteers using different Cryptosporidium parvum isolates (IOWA, TAMU, and UCP). The study data were previously analyzed for median infectious dose (ID50) using a simple cumulative percent endpoi...

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

    EPA Science Inventory

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

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

  10. 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...

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

    EPA Science Inventory

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

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

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

    PubMed Central

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

    2004-01-01

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

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

    PubMed

    Hayes, Lawrence D; Morse, Christopher I

    2010-03-01

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

  14. Dose Response Effects of Dermally applied Diethanolamine on Neurogenesis in Fetal Mouse Hippocampus and Potential Exposure of Humans

    PubMed Central

    Craciunescu, Corneliu N.; Niculescu, Mihai D.; Guo, Zhong; Johnson, Amy R.; Fischer, Leslie; Zeisel, Steven H.

    2009-01-01

    Diethanolamine (DEA) is a common ingredient of personal care products. Dermal administration of DEA diminishes hepatic stores of the essential nutrient choline and alters brain development. We previously reported that 80 mg/kg/day of DEA during pregnancy in mice reduced neurogenesis and increased apoptosis in the fetal hippocampus. This study was designed to establish the dose-response relationships for this effect of DEA. Timed-pregnant C57BL/6 mouse dams were dosed dermally from gestation day 7–17 with DEA at 0 (controls), 5, 40, 60, and 80 mg/kg body/day. Fetuses (embryonic day 17 [E17]) from dams treated dermally with 80 mg/kg body/day DEA had decreased neural progenitor cell mitosis at the ventricular surface of the ventricular zone (hippocampus, 54.1 ± 5.5%; cortex, 58.9 ± 6.8%; compared to controls; p < 0.01). Also, this dose of DEA to dams increased rates of apoptosis in E17 fetal hippocampus (to 177.2 ± 21.5% of control; measured using activated caspase-3; p < 0.01). This dose of DEA resulted in accumulation of DEA and its metabolites in liver and in plasma. At doses of DEA less than 80 mg/kg body/day to dams, there were no differences between treated and control groups. In a small group of human subjects, dermal treatment for 1 month with a commercially available skin lotion containing 1.8 mg DEA per gram resulted in detectable plasma concentrations of DEA and dimethyldiethanolamine, but these were far below those concentrations associated with perturbed brain development in the mouse. PMID:18948303

  15. Radiation response of industrial materials: Dose-rate and morphology implications

    NASA Astrophysics Data System (ADS)

    Berejka, Anthony J.

    2007-08-01

    Industrial uses of ionizing radiation mostly rely upon high current, high dose-rate (100 kGy/s) electron beam (EB) accelerators. To a lesser extent, industry uses low dose-rate (2.8 × 10-3 kGy/s) radioactive Cobalt-60 as a gamma source, generally for some rather specific purposes, as medical device sterilization and the treatment of food and foodstuffs. There are nearly nine times as many (∼1400) high current EB units in commercial operation than gamma sources (∼160). However, gamma sources can be easily scaled-down so that much research on materials effects is conducted using gamma radiation. Likewise, laboratories are more likely to have very low beam current and consequently low dose-rate accelerators such as Van de Graaff generators and linear accelerators. With the advent of very high current EB accelerators, X-ray processing has become an industrially viable option. With X-rays from high power sources, dose-rates can be modulated based upon accelerator power and the attenuation of the X-ray by the distance of the material from the X-ray target. Dose and dose-rate dependence has been found to be of consequence in several commercial applications which can employ the use of ionizing radiation. The combination of dose and dose-rate dependence of the polymerization and crosslinking of wood impregnants and of fiber composite matrix materials can yield more economically viable results which have promising commercial potential. Monomer and oligomer structure also play an important role in attaining these desirable results. The influence of morphology is shown on the radiation response of olefin polymers, such as ethylene, propylene and isobutylene polymers and their copolymers. Both controlled morphology and controlled dose-rate have commercial consequences. These are also impacted both by the adroit selection of materials and through the possible use of X-ray processing.

  16. West Nile Virus Infection in American Robins: New Insights on Dose Response

    PubMed Central

    VanDalen, Kaci K.; Hall, Jeffrey S.; Clark, Larry; McLean, Robert G.; Smeraski, Cynthia

    2013-01-01

    West Nile virus (WNV) is a vector-borne pathogen that was first detected in the United States in 1999. The natural transmission cycle of WNV involves mosquito vectors and avian hosts, which vary in their competency to transmit the virus. American robins are an abundant backyard species in the United States and appear to have an important role in the amplification and dissemination of WNV. In this study we examine the response of American robins to infection with various WNV doses within the range of those administered by some natural mosquito vectors. Thirty American robins were assigned a WNV dosage treatment and needle inoculated with 100.95 PFU, 101.26 PFU, 102.15 PFU, or 103.15 PFU. Serum samples were tested for the presence of infectious WNV and/or antibodies, while oral swabs were tested for the presence of WNV RNA. Five of the 30 (17%) robins had neutralizing antibodies to WNV prior to the experiment and none developed viremia or shed WNV RNA. The proportion of WNV-seronegative birds that became viremic after WNV inoculation increased in a dose dependent manner. At the lowest dose, only 40% (2/5) of the inoculated birds developed productive infections while at the highest dose, 100% (7/7) of the birds became viremic. Oral shedding of WNV RNA followed a similar trend where robins inoculated with the lower two doses were less likely to shed viral RNA (25%) than robins inoculated with one of the higher doses (92%). Viremia titers and morbidity did not increase in a dose dependent manner; only two birds succumbed to infection and, interestingly, both were inoculated with the lowest dose of WNV. It is clear that the disease ecology of WNV is a complex interplay of hosts, vectors, and viral dose delivered. PMID:23844218

  17. Relationships between hemodynamic, hemorheological and metabolic responses during exercise.

    PubMed

    Connes, Philippe; Tripette, Julien; Mukisi-Mukaza, Martin; Baskurt, Oguz K; Toth, Kalman; Meiselman, Herbert J; Hue, Olivier; Antoine-Jonville, Sophie

    2009-01-01

    Aerobic performance is dependent on both cardio-respiratory and peripheral factors with hemodynamic parameters playing a major role. However, whether blood rheology might affect aerobic performance through an effect on hemodynamic factors is not known. The aim of the present study was to assess the relationships between hemodynamic, hemorheological and metabolic parameters in response to a sub-maximal cycling exercise protocol consisting of three successive levels of nine min duration (50, 100 and 150 W). Ten young sportsmen participated in the present study. Mean arterial pressure (MAP) was measured manually, with thoracic impedance used to monitor cardiac output (Qc): systemic vascular resistance (SVR) was then calculated. Whole blood viscosity (etab) was measured and used to calculate systemic vascular hindrance. Hematocrit (Hct) was determined by micro-centrifugation and red blood cell (RBC) deformability (EI) was determined by ecktacytometry. A breath-by-breath gas analyzer was used to measure oxygen uptake (VO2); the Fick equation was used to calculate arterio-venous oxygen difference [(a-v)O(2)] from VO(2) and Qc. All measurements were performed at rest, during exercise and during recovery. Compared to baseline, Qc, MAP, Hct, EI, VO(2), and (a-v)O(2) increased during exercise. etab increased above baseline only at 150 W and remained elevated during recovery; the increase in etab during the last level of exercise was associated with a decrease of SVR and systemic vascular hindrance. There was a significant negative correlation between EI and SVR (r=-0.35, p<0.01) and a significant positive relationship between EI and (a-v)O(2) (r=0.35, p<0.01) and between EI and VO(2) (r=0.37, p<0.01) across all exercise workloads, thus suggesting a potential role for RBC deformability as a factor affecting aerobic performance via oxygen delivery to tissues. These data lend support to the concept that hemorheological parameters may contribute to hemodynamic and cardio

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

    SciTech Connect

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

    2005-11-01

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

  19. Age-related changes in the relationship between auditory brainstem responses and envelope-following responses.

    PubMed

    Parthasarathy, Aravindakshan; Datta, Jyotishka; Torres, Julie Ann Luna; Hopkins, Charneka; Bartlett, Edward L

    2014-08-01

    Hearing thresholds and wave amplitudes measured using auditory brainstem responses (ABRs) to brief sounds are the predominantly used clinical measures to objectively assess auditory function. However, frequency-following responses (FFRs) to tonal carriers and to the modulation envelope (envelope-following responses or EFRs) to longer and spectro-temporally modulated stimuli are rapidly gaining prominence as a measure of complex sound processing in the brainstem and midbrain. In spite of numerous studies reporting changes in hearing thresholds, ABR wave amplitudes, and the FFRs and EFRs under neurodegenerative conditions, including aging, the relationships between these metrics are not clearly understood. In this study, the relationships between ABR thresholds, ABR wave amplitudes, and EFRs are explored in a rodent model of aging. ABRs to broadband click stimuli and EFRs to sinusoidally amplitude-modulated noise carriers were measured in young (3-6 months) and aged (22-25 months) Fischer-344 rats. ABR thresholds and amplitudes of the different waves as well as phase-locking amplitudes of EFRs were calculated. Age-related differences were observed in all these measures, primarily as increases in ABR thresholds and decreases in ABR wave amplitudes and EFR phase-locking capacity. There were no observed correlations between the ABR thresholds and the ABR wave amplitudes. Significant correlations between the EFR amplitudes and ABR wave amplitudes were observed across a range of modulation frequencies in the young. However, no such significant correlations were found in the aged. The aged click ABR amplitudes were found to be lower than would be predicted using a linear regression model of the young, suggesting altered gain mechanisms in the relationship between ABRs and FFRs with age. These results suggest that ABR thresholds, ABR wave amplitudes, and EFRs measure complementary aspects of overlapping neurophysiological processes and the relationships between these

  20. Deriving a dosage-response relationship for community response to high-energy impulsive noise

    NASA Technical Reports Server (NTRS)

    Fidell, Sanford; Pearsons, Karl S.

    1994-01-01

    The inability to systematically predict community response to exposure to sonic booms (and other high energy impulsive sounds) is a major impediment to credible analyses of the environmental effects of supersonic flight operations. Efforts to assess community response to high energy impulsive sounds are limited in at least two important ways. First, a paucity of appropriate empirical data makes it difficult to infer a dosage-response relationship by means similar to those used in the case of general transportation noise. Second, it is unclear how well the 'equal energy hypothesis' (the notion that duration, number, and level of individual events are directly interchangeable determinants of annoyance) applies to some forms of impulsive noise exposure. Some of the issues currently under consideration by a CHABA working group addressing these problems are discussed. These include means for applying information gained in controlled exposure studies about different rates of growth of annoyance with impulsive and non-impulsive sound exposure levels, and strategies for developing a dosage-response relationship in a data-poor area.

  1. Association of dose escalation of octreotide long-acting release on clinical symptoms and tumor markers and response among patients with neuroendocrine tumors.

    PubMed

    Al-Efraij, Khalid; Aljama, Mohammed A; Kennecke, Hagen Fritz

    2015-06-01

    Patients with nonresectable metastatic neuroendocrine tumors (NETs) experience symptoms of hormone hypersecretion including diarrhea, flushing, and bronchoconstriction, which can interfere with quality of life [Anthony and Vinik (2011) Pancreas, 40:987]. Treatment with a long-acting release formulation of octreotide, a somatostatin analog, can help to alleviate these symptoms. Although high doses of octreotide are often required for adequate symptom control, the relationship between octreotide dose escalation and symptom control in the NET context is not well quantified in the literature. A retrospective chart review was conducted of nonresectable metastatic NET patients who received a dose greater than 30 mg intramuscular octreotide long-acting formulation (O-LAR) at any time between January 2005 and December 2011 at the British Columbia Cancer Agency (BCCA). The association between dose escalation of O-LAR, chromogranin A (CGA), 24-h urine 5-hydoxyindoacetate (5-HIAA), symptom control, and radiological progression was explored. Dose escalation of O-LAR was associated with improved symptom control in NET patients who were refractory to the standard dose levels. Reduction of serum CGA & 5-HIAA levels by at least 10% was observed in 31% and 23% respectively. Retrospective review of imaging did not document any reductions in tumor volume. Higher doses of O-LAR are associated with improved symptom control in NET patients. The variability in tumor marker levels in response to O-LAR dose escalation may indicate that tumor marker levels may not be an accurate assessment of therapeutic efficacy. PMID:25727756

  2. 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.

  3. Multiple myeloma among atomic bomb survivors in Hiroshima and Nagasaki, 1950-76: relationship to radiation dose absorbed by marrow

    SciTech Connect

    Ichimaru, M.; Ishimaru, T.; Mikami, M.; Matsunaga, M.

    1982-08-01

    The relationship between atomic bomb exposure and the incidence of multiple myeloma has been examined in a fixed cohort of atomic bomb survivors and controls in the life-span study sample for Hiroshima and Nagasaki. From October 1950 to December 1976, 29 cases of multiple myeloma were confirmed in this sample. Our analysis shows that the standardized relative risk (RR) adjusted for city, sex, and age at the time of bombings (ATB) increased with marrow-absorbed radiation dose. The increased RR does not appear