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Results for “benchmark dose analysis”

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PubMed2006

Surveillance of antibiotic use in hospitals: methods, trends and targets.

A standardised antibiotic surveillance system is an essential requirement of all antibiotic control strategies. Antibiotic use can be quantified accurately using patient-level surveillance, although this is not feasible for most hospitals. Instead, population-level surveillance is a more realistic alternative for ongoing and systematic monitoring of antibiotic use. Monitoring of aggregate, ward-supply data on a monthly basis, stratification by patient care area, and analysis by the anatomical therapeutic chemical/defined daily dose (ATC/DDD) system, adjusting for bed-occupancy, provides a clear picture of antibiotic consumption density and time-trends within a hospital. When usage rates are supplemented and interpreted according to changes in hospital resource indicators, benchmarking is facilitated. This provides an efficient tool for triggering and targeting antibiotic control interventions.

Anti-Bacterial Agents↗

PubMed2000

Fitting and benchmarking of dosimetry data for new brachytherapy sources.

New source designs of encapsulated low-energy gamma emitting nuclides for permanent implants require dosimetric analysis and calibration standardization. The dosimetry measurements can be incorporated into a treatment planning system by fitting the data. The use of a fitting function whose behavior at range limits mimics the physical phenomena, using as few parameters as possible, eliminates noisy outliers and lends credence to calculations beyond the measured range. Clinical implementation of the new sources also requires benchmarking against existing sources, where the current clinical experience lies. We present an analysis of measured dosimetry data for three brachytherapy sources recently available from North American Scientific, Inc. (North Hollywood, CA): 103Pd source model MED3633 ("PdGold"), 125I source models MED3631-A/M ("IoGold-AM") and MED3631-A/S ("IoGold-AS"). Using the formalism of the Interstitial Collaborative Working Group (ICWG) the radial dose function, g(r), the anisotropy function, F(r, theta), and the anisotropy factor, phi an(r), were previously evaluated from measurements of each source design. In this report we use fitting functions whose forms are chosen to approach reasonable values at data limits. These forms are quite similar to those used in a previous analysis of TG43 Iodine and palladium compendium data. Fitting parameter results for each function are provided for each brachytherapy source model. Fit-data discrepancies are smaller than measurement uncertainties, meaning that incorporation into treatment planning systems will not introduce significant errors in clinical use. Current clinical experience is based on the Theragenics (Norcross, GA) 103Pd seed ("PdThera"), and the Nycomed-Amersham (Arlington Heights, IL) 125I seed models 6711 ("6711") and 6702 ("6702"). The new sources are benchmarked against these seeds.

Anisotropy↗

PubMedDate not supplied

Microarray-based compendium of hepatic gene expression profiles for prototypical ADME gene-inducing compounds in rats and mice in vivo.

To examine species-specific aspects of the induction of absorption, distribution, metabolism and excretion (ADME)-related genes, we used 25 000 gene oligonucleotide microarrays to construct a rodent gene-response compendium that compared hepatic gene expression profiles and developed consensus aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR) and pregnane X-receptor (PXR) ligand signatures relevant to drug clearance. Twenty-six inducer compounds were chosen from the literature. Rats and mice received one of six dose levels (log2 dose escalation, 32-fold dose range) of each compound daily for 3 days. Animals were necropsied 6-9 h after the last dose, and tissues were collected for RNA analysis. Hepatic gene expression profiles were obtained using Rosetta Resolver expression analysis system, and ADME-related genes were extracted. Cross-talk among nuclear receptors or hepatoxicity at high dose levels resulted in large signatures (usually >1000 genes at p < 0.01) for most compounds. After ADME gene transcript enrichment, agglomerative clustering separated AhR ligands from CAR/PXR ligands, but it was difficult to distinguish CAR from PXR ligands. Consensus signatures were derived from groups of AhR, CAR and PXR ligands; and cross-talk among responding genes was determined. Many compounds had distinct log dose-response profiles, and relative potencies for ligands were established. Robust responses by CYP1A1, CYP2B10 (CAR responsive in mice) and CYP2B15 (CAR responsive in rats) and CYP3A1 (PXR responsive in rats) were used to benchmark the relative potency of different ligands and to determine the relative selectivity for AhR, CAR or PXR. By using a compendium of gene expression profiles, we defined species-specific induction patterns across the ADME transcriptome.

Animals↗

PubMed2005

Health effects of cadmium exposure in the general environment in Japan with special reference to the lower limit of the benchmark dose as the threshold level of urinary cadmium.

OBJECTIVES: This study investigates renal dysfunction in areas without known environmental cadmium pollution and calculates the threshold level of urinary cadmium. METHODS: Urinary total protein, beta2-microglobulin (beta2-MG), and N-acetyl-beta-D-glucosaminidase (NAG), used as indicators of renal dysfunction, and urinary cadmium concentration, used as an indicator of cadmium exposure, were measured in two sets of 24-hour urine samples from each of 828 participants (410 men, 418 women), aged 40-59 years and living in three areas without any known environmental cadmium pollution. In multiple regression and logistic regression analyses the association between indicators of cadmium exposure and indicators of renal dysfunction were studied. The lower 95% confidence limit of the dose (benchmark dose) corresponding to a 5% (BMDL5) or 10% (BMDL10) level of each indicator of renal dysfunction above the background level) was calculated as the threshold level of urinary cadmium. RESULTS: With all the expressed units [g creatinine(-1) and day(-1)] in the multiple regression analysis, the partial regression coefficients showed a significant association between urinary cadmium concentration and total protein, beta2-MG, and NAG for both genders, except for total protein for women (g creatinine(-1) and day(-1). The same results were obtained for both genders in the logistic regression analysis. The BMDL10 was 0.6-1.2 microg/g creatinine and 0.8-1.6 microg/day for the men and 1.2-3.6 microg/g creatinine, and 0.5-4.7 microg/day for the women. CONCLUSIONS: Cadmium exposure and the levels of the indicators of renal dysfunction were associated among the men and women aged 40-59 years in areas without any known environmental cadmium pollution. The threshold level of urinary cadmium in Japan seems to be almost the same as in Belgium and Sweden.

Acetylglucosaminidase↗

PubMed2003

Cumulative organophosphate pesticide exposure and risk assessment among pregnant women living in an agricultural community: a case study from the CHAMACOS cohort.

Approximately 230,000 kg of organophosphate (OP) pesticides are applied annually in California's Salinas Valley. These activities have raised concerns about exposures to area residents. We collected three spot urine samples from pregnant women (between 1999 and 2001) enrolled in CHAMACOS (Center for the Health Assessment of Mothers and Children of Salinas), a longitudinal birth cohort study, and analyzed them for six dialkyl phosphate metabolites. We used urine from 446 pregnant women to estimate OP pesticide doses with two deterministic steady-state modeling methods: method 1, which assumed the metabolites were attributable entirely to a single diethyl or dimethyl OP pesticide; and method 2, which adapted U.S. Environmental Protection Agency (U.S. EPA) draft guidelines for cumulative risk assessment to estimate dose from a mixture of OP pesticides that share a common mechanism of toxicity. We used pesticide use reporting data for the Salinas Valley to approximate the mixture to which the women were exposed. Based on average OP pesticide dose estimates that assumed exposure to a single OP pesticide (method 1), between 0% and 36.1% of study participants' doses failed to attain a margin of exposure (MOE) of 100 relative to the U.S. EPA oral benchmark dose(10) (BMD(10)), depending on the assumption made about the parent compound. These BMD(10) values are doses expected to produce a 10% reduction in brain cholinesterase activity compared with background response in rats. Given the participants' average cumulative OP pesticide dose estimates (method 2) and regardless of the index chemical selected, we found that 14.8% of the doses failed to attain an MOE of 100 relative to the BMD(10) of the selected index. An uncertainty analysis of the pesticide mixture parameter, which is extrapolated from pesticide application data for the study area and not directly quantified for each individual, suggests that this point estimate could range from 1 to 34%. In future analyses, we will use pesticide-specific urinary metabolites, when available, to evaluate cumulative OP pesticide exposures.

Adolescent↗

PubMed2005

Radiation shielding and dosimetry experiments updates in the SINBAD database.

The Shielding Integral Benchmark Archive Database (SINBAD) is an internationally established set of radiation shielding and dosimetry data related to experiments relevant in reactor shielding, fusion blanket neutronics and accelerator shielding. In addition to the characterisation of the radiation source, it describes shielding materials and instrumentation and the relevant detectors. The experimental results, be it dose or reaction rates, or unfolded spectra, are presented in tabular ASCII form that can easily be exported to different computer environments for further use. Most sets in SINBAD also contain the computer model used for the interpretation of the experiment and, where available, results from uncertainty analysis. This is an international effort between the Organization for Economic Cooperation and Development, Nuclear Energy Agency Data Bank (http://www.nea.fr/html/databank/) (OECD/NEA Data Bank) and Oak Ridge National Laboratory, Radiation Safety Information Computational Center (http://www-rsicc.ornl.gov/rsic.html) (ORNL/RSICC). Cooperation from many organisations, authors and benchmark analysts have helped SINBAD become a 'living database'--one which involves continuous information updates, preservation and additions of nuclear benchmarks in the areas of fusion, fission and accelerator science and engineering. This paper focuses on the increased comprehensiveness of experiments that have been carried out in recent years and the validation of computer code and cross section library using these experiments.

Database Management Systems↗

PubMed2000

The cost-effectiveness and cost-utility of high-dose palliative radiotherapy for advanced non-small-cell lung cancer.

PURPOSE: To compute cost-effectiveness/cost-utility (CE/CU) ratios, from the treatment clinic and societal perspectives, for high-dose palliative radiotherapy treatment (RT) for advanced non-small-cell lung cancer (NSCLC) against best supportive care (BSC) as comparator, and thereby demonstrate a method for computing CE/CU ratios when randomized clinical trial (RCT) data cannot be generated. METHODS AND MATERIALS: Unit cost estimates based on an earlier reported 1989-90 analysis of treatment costs at the Vancouver Island Cancer Centre, Victoria, British Columbia, Canada, are updated to 1997-1998 and then used to compute the incremental cost of an average dose of high-dose palliative RT. The incremental number of life days and quality-adjusted life days (QALDs) attributable to treatment are from earlier reported regression analyses of the survival and quality-of-life data from patients who enrolled prospectively in a lung cancer management cost-effectiveness study at the clinic over a 2-year period from 1990 to 1992. RESULTS: The baseline CE and CU ratios are $9245 Cdn per life year (LY) and $12,836 per quality-adjusted life year (QALY), respectively, from the clinic perspective; and $12,253/LY and $17,012/QALY, respectively, from the societal perspective. Multivariate sensitivity analysis for the CE ratio produces a range of $5513-28,270/LY from the clinic perspective, and $7307-37,465/LY from the societal perspective. Similar calculations for the CU ratio produce a range of $7205-37, 134/QALY from the clinic perspective, and $9550-49,213/QALY from the societal perspective. CONCLUSION: The cost effectiveness and cost utility of high-dose palliative RT for advanced NSCLC compares favorably with the cost effectiveness of other forms of treatment for NSCLC, of treatments of other forms of cancer, and of many other commonly used medical interventions; and lies within the US $50, 000/QALY benchmark often cited for cost-effective care.

British Columbia↗

PubMed2002

Dose-response modeling of continuous endpoints.

A family of (nested) dose-response models is introduced herein that can be used for describing the change in any continuous endpoint as a function of dose. A member from this family of models may be selected using the likelihood ratio test as a criterion, to prevent overparameterization. The proposed methodology provides for a formal approach of model selection, and a transparent way of assessing the benchmark dose. Apart from a number of natural constraints, the model expressions follow from an obvious way of quantifying differences in sensitivity between populations. As a consequence, dose-response data that relate to both sexes can be efficiently analyzed by incorporating the data from both sexes in the same analysis, even if the sexes are not equally sensitive to the compound studied. The idea of differences in sensitivity is closely related to the assessment factors used in risk assessment. Thus, the models are directly applicable to estimating such factors, if data concerning populations to be compared are available. Such information is valuable for further validation or adjustment of default assessment factors, as well as for informing distributional assessment factors in a probabilistic risk assessment. The various applications of the proposed methodology are illustrated by real data sets.

Animals↗

PubMed2005

A method for benchmarking CT scanners.

This study involved the development of an objective method to compare the performance of five CT scanners for the purpose of benchmarking. The method used to assess the scanners was to determine the dose-normalised noise at a spatial resolution of 5.5 cm(-1). This gave a dose-normalised percent noise between 0.37% and 0.76%. The scanners were also assessed for radiation dose to patients undergoing abdomen and head CT examinations. Patients' dose-length product (DLP) for the abdomen clinical examinations varied from 305 to 685 mGy-cm, and for the head clinical examinations from 333 to 900 mGy-cm. The study results demonstrated that the comparison of dose and spatial resolution normalised percent noise levels is a useful method of comparing CT scanner performance.

Australia↗

PubMed1990

Impact of intravenous thrombolysis on short-term coronary revascularization rates. A meta-analysis.

Evidence of the potential impact of intravenous thrombolytic therapy on short-term revascularization rates among patients with acute myocardial infarction was sought. Because nonrandomized comparisons with conventional treatment would be subject to various confounders, a meta-analysis of randomized controlled trials was performed. Seven trials were included, applying standard doses of either tissue plasminogen activator or streptokinase without an aggressive revascularization protocol. Follow-up ranged from 14 to 30 days. The revascularization rates among treated patients in all trials were lower than in the conservative arm of the Thrombolysis in Myocardial Infarction Phase II trial, which established the current procedural benchmarks for postthrombolysis management. However, the aggregate volume of bypass surgery and angioplasty in patients treated with tissue plasminogen activator was more than double that of controls (odds ratio, 2.25; 95% confidence interval, 1.31 to 3.94), with a smaller but still significant increase for streptokinase-treated patients (odds ratio, 1.66; 95% confidence interval, 1.08 to 2.59). Combining all trials, the increase in mechanical revascularization was 80% (95% confidence interval, 33% to 144%). Thus, for patterns of practice currently accepted in North America, intravenous thrombolysis for myocardial infarction leads to a significant short-term increase in clinical and angiographic indications for revascularization as compared with conventional treatment.

Angiography↗

PubMed2006

A probabilistic framework for non-cancer risk assessment.

Risk assessment involves an analysis of the relationship between exposure and health related outcomes to derive an allowable exposure level or to estimate a low-dose risk. Acceptable levels of human exposure for non-cancer effects generally are derived by dividing an experimental no-observed-adverse-effect-level or a lower confidence limit benchmark dose by a product of several uncertainty factors. This paper presents a hierarchical modeling framework for a probabilistic approach to non-cancer risk assessment. The hierarchical model integrates the distributions of uncertainty factors and the distribution of the actual exposure level to construct the dose-response model for the proportion of population at risk and the dose-response model for the expected proportion of population at risk for a given exposure distribution. The proposed approach is based on the use of the BMDL (lower confidence limit on the benchmark dose) as a POD (point of departure) for risk assessment of non-cancer effects.

Animals↗

PubMed2001

The benchmark approach applied to a 28-day toxicity study with Rhodorsil Silane in rats. the impact of increasing the number of dose groups.

The OECD study design, aimed at obtaining a no-observed-adverse-effect level (NOAEL), may be suboptimal for deriving a benchmark dose. Therefore the present subacute (28-day) study was carried out to evaluate a multiple dose study design and to compare the results with the common OECD design. Seven groups of 10 female rats each were intragastrically administered corn oil without (controls) or with 50, 150, 300, 450, 600 or 750 mg Rhodorsil Silane/kg body weight/day, once daily (7 days/week) for 4 weeks. From the complete dataset, two subsets were selected, one representing a study design with seven dose groups of five animals (7 x 5 design), the other representing a study design with four dose groups of 10 animals (4 x 10 design). Under the conditions of the present study, the NOAEL for Rhodorsil Silane 198 was assessed at 50 mg/kg body weight/day, based on the data of the 4 x 10 design. The benchmark approach resulted in a benchmark dose of 19 mg/kg body weight/day, based on the data of the 7 x 5 design. Comparison of the results demonstrated that the multiple dose (7 x 5) design led to a more reliable result than the OECD (4 x 10) design, despite the smaller total number of animals. The dose-response analysis showed that at "the NOAEL" the effect on relative spleen weight was larger than 10%, illustrating that at the NOAEL, adverse effects may occur.

Alanine Transaminase↗

PubMed2006

Approaches to extrapolating animal toxicity data on organic solvents to public health.

Synthesizing information about the acute neurotoxicity of organic solvents into predictive relationships between exposure and effect in humans is difficult because (1) data are usually derived from experimental animals whose sensitivity to the chemical relative to humans is unknown; (2) the specific endpoints measured in laboratory animals seldom translate into effects of concern in humans; and (3) the mode of action of the chemical is rarely understood. We sought to develop approaches to estimate the hazard and cost of exposure to organic solvents, focusing on the acute behavioral effects of toluene in rats and humans. Available published data include studies of shock avoidance behavior in rats and choice reaction time in humans. A meta-analysis of these data suggested that a 10% change in rat avoidance behavior occurs at a blood concentration of toluene 25 times higher than the concentration at which a 10% change in human choice reaction time occurs. In contrast, our in vitro studies of nicotinic acetylcholine receptors indicated that human and rat receptors do not differ in sensitivity to toluene. Analysis of other dose-response relationships for visual and cognitive functions in rats suggests that the apparent difference between rats and humans may be driven by the specific endpoints measured in the two species rather than by inherent differences in sensitivity to toluene. We also explored the hypothesis that dose-equivalence relationships may be used to compare the societal costs of two chemicals. For example, ethanol-induced changes in choice reaction time, for which societal costs are estimatable, may be used as a benchmark effect for estimating the monetary benefits of controlling exposure to organic solvents. This dose-equivalence method is applicable for solvents because this set of data fulfills three important assumptions about equivalence relationships based on a single effect: (1) a common dose metric (concentration of the chemical in the brain); (2) a common effect to provide a linking variable (choice reaction time); and (3) a common mode of action (interference with neuronal ion channel function).

Animals↗

PubMed2001

A randomization test-based method for risk assessment in neurotoxicology.

A current trend in risk assessment for systemic toxicity (noncancer) endpoints is to utilize the observable range of the dose-effect curve in order to estimate the likelihood of obtaining effects at lower concentrations. Methods to accomplish this endeavor are typically based on variability in either the effects of fixed doses (benchmark approaches), or on variability in the doses producing a fixed effect (probabilistic or tolerance-distribution approaches). The latter method may be particularly desirable because it can be used to determine variability in the effect of an agent in a population, which is an important goal of risk assessment. This method of analysis, however, has typically been accomplished using dose-effect data from individual subjects, which can be impractical in toxicology. A new method is therefore presented that can use traditional groups-design data to generate a set of dose-effect functions. Population tolerances for a specific effect can then be estimated from these model dose-effect functions. It is based on the randomization test, which assesses the generality of a data set by comparing it to a data set constructed from randomized combinations of single point estimates. The present article describes an iterative line-fitting program that generates such a data set and then uses it to provide risk assessments for two pesticides, triadimefon and carbaryl. The effects of these pesticides were studied on the locomotor activity of laboratory rats, a common neurobehavioral end point. Triadimefon produced dose-dependent increases in activity, while carbaryl produced dose-dependent decreases in activity. Risk figures derived from the empirical distribution of individual dose-effect functions were compared to those from the iterative line-fitting program. The results indicate that the method generates comparable risk figures, although potential limitations are also described.

Animals↗

PubMed2004

Optimization of the epithermal neutron beam for Boron Neutron Capture Therapy at the Brookhaven Medical Research Reactor.

The use of epithermal neutron beam in clinical trials of Boron Neutron Capture Therapy for patients with malignant brain tumors had been carried out for half a decade at the Brookhaven's Medical Reactor. The decision to permanently close this reactor in 2000 cut short the efforts to implement a new conceptual design to optimize this beam in preparation for use with possible new BNCT protocols. Details of the conceptual design to produce a highly intensified and focused neutron beam with less gamma and neutron contamination in tissues are presented here for their potential applicability to other reactor facilities. Neutron-photon coupled Monte Carlo calculations were used to predict the flux, current, heating, and absorbed dose produced by the proposed design. The results were benchmarked by the dose rate and flux measurements taken at the facility then in use.

Academies and Institutes↗

PubMed1991

Pretreatment and treatment factors associated with improved outcome in squamous cell carcinoma of the uterine cervix: a final report of the 1973 and 1978 patterns of care studies.

The Patterns of Care Study (PCS) conducted two national surveys of patients treated in 1973 and 1978 for squamous cell cancer of the uterine cervix. In addition, a survey of patients treated in 1973 from selected large facilities was conducted to establish outcome with "optimal" radiotherapy. The large facility survey consistently reported improved outcome compared to both national average surveys when analyzed by stage and other significant pretreatment factors. That improved outcome was associated with the paracentral (PCS point A) dose and the use of intracavitary irradiation. In this study, we report the pretreatment and treatment factors associated with improved outcome in squamous cell carcinoma of the uterine cervix by analysis of the 1973 and 1978 PCS data. Pretreatment factors associated with improved pelvic control in multivariate analysis include higher Karnofsky Performance Status (KPS) (Stage I and II), older age (Stage I and II), unilateral parametrial involvement (Stage IIB), and unilateral sidewall involvement (Stage III). The only treatment factor associated with improved pelvic control in multivariate analysis is the use of intracavitary irradiation. However, a dose response for infield pelvic control was demonstrated only in Stage III cervix cancer with the highest rate of pelvic control with paracentral (PCS point A) dose greater than 8500 cGy. Multivariate analysis revealed that unilateral parametrial involvement for Stage IIB and unilateral sidewall involvement for Stage III are significant positive prognostic factors with respect to survival after treatment with radiotherapy. No FIGO substage significantly affected survival after radiotherapy. Although FIGO staging is the single most important pretreatment prognostic factor with respect to survival and infield pelvic failure, FIGO substaging deserves reappraisal and further refinement. Major complications were seen in only 9.5% of patients treated with radiotherapy and were stage but not survey related. There is a significant relationship between PCS point A dose and complications with the highest rate of complications for PCS point A dose greater than 8500 cGy. A significant relationship between lateral (external iliac lymph nodes or PCS point P) dose and major complications is also found, and doses greater than 5000 cGy are associated with a significant increase in complications. The PCS has established two sequential national benchmarks of treatment outcome for squamous cell carcinoma of the uterine cervix treated with radiotherapy with respect to survival, infield pelvic control, and complications.(ABSTRACT TRUNCATED AT 400 WORDS)

Age Factors↗

PubMed1994

Summary of the workshop on issues in risk assessment: quantitative methods for developmental toxicology.

This report summarizes the proceedings of a conference on quantitative methods for assessing the risks of developmental toxicants. The conference was planned by a subcommittee of the National Research Council's Committee on Risk Assessment Methodology in conjunction with staff from several federal agencies, including the U.S. Environmental Protection Agency, U.S. Food and Drug Administration, U.S. Consumer Products Safety Commission, and Health and Welfare Canada. Issues discussed at the workshop included computerized techniques for hazard identification, use of human and animal data for defining risks in a clinical setting, relationships between end points in developmental toxicity testing, reference dose calculations for developmental toxicology, analysis of quantitative dose-response data, mechanisms of developmental toxicity, physiologically based pharmacokinetic models, and structure-activity relationships. Although a formal consensus was not sought, many participants favored the evolution of quantitative techniques for developmental toxicology risk assessment, including the replacement of lowest observed adverse effect levels (LOAELs) and no observed adverse effect levels (NOAELs) with the benchmark dose methodology.

Animals↗

PubMed2002

A technique for microsecond heating and cooling of a thin (submicron) biological sample.

Temperature excursions of short duration are useful in exploring the effects of stress on biological systems. Stress will affect the conformation of biological molecules such as proteins, which will lead to an effect on their function. The feasibility of generating such temperature excursions is demonstrated by solving the heat diffusion equation for an aqueous layer on a silicon wafer. The silicon is rapidly heated by a laser pulse and also acts as a heat sink to quench the temperature rise. An oxide layer was used to limit the maximum temperature attained by the sample. We show that exposures above a 50 degrees C benchmark can be confined to times less than 5 micros.

Cold Temperature↗