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Results for “benchmark dose analysis”

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PubMed1984

Patterns of care outcome studies: results of the national practice in adenocarcinoma of the prostate.

The Patterns of Care Study reviewed the processes and outcome of 682 patients with carcinoma of the prostate treated with radiation therapy from 1973-1976. The study and patient sampling were designed to reflect a valid representation of how prostate cancer is treated by radiation oncologists in the United States. The outcome results represent national benchmarks. The three year actuarial survival was 91% for Stage A, 88% for Stage B, and 76% for Stage C. The three year relapse free survival rate was 85% for Stage A, 77% for Stage B, and 59% for Stage C. The infield recurrence rates were: Stage A--4%, Stage B--9%, and Stage C--20%. Stage, grade, elevated serum acid phosphatase, Karnofsky performance status, previous hormonal therapy, age, and prior transurethral resection were identified by multivariate regression analysis to be important independent prognostic variables. Local control was related to the dose of the primary site, paraprostatic region, and pelvic sidewall. Local control was significantly improved if the facility's best treatment equipment was a linear accelerator. Major complications occurred in 9% of patients with Stage A, 2% of Stage B, and 6% with Stage C disease. Complications were related to dose and treatment technique. The Patterns of Care Process Survey identified that only 60% of patients surveyed had the necessary pretreatment evaluation studies required for best current management of adenocarcinoma of the prostate. Variance occurred within each stratum of facilities sampled. Strict attention to the details of evaluation of therapy will help to enhance the delivery of optimal radiation therapy in the management of patients with carcinoma of the prostate.

Adenocarcinoma↗

PubMed2005

Automatic selection of non-coplanar beam directions for three-dimensional conformal radiotherapy.

An algorithm is described, based on ray-tracing and the beam's-eye-view, that exhaustively searches all permitted beam directions. The evaluation of the search is based on a general cost function that can be adapted to the clinical objectives by means of parameters and weighting factors. The approach takes into account the constraints of the linear accelerator by discarding beam directions that are not permitted. A sensitivity analysis was carried out to determine appropriate parameters for different sized organs, and a prostate case was used to benchmark the approach. The algorithm was also applied to two clinical cases (brain and sinus) to test the benefits of the approach compared with manual angle selection. The time to perform a beam direction search was approximately 2 min for the coplanar and 12 min for the non-coplanar beam space. The angles obtained for the prostate case compared well with reports in the literature. For the brain case, the mean dose to the right and left optic nerves was reduced by 12% and 50%, respectively, whilst the target dose uniformity was improved. For the sinus case, the mean doses to the right and left parotid glands were reduced by 54% and 46%, respectively, to the right and left optic nerves by 37% and 62%, respectively, and to the optic chiasm by 39%, whilst the target dose uniformity was also improved. For the clinical cases the plans based on optimized beam directions were simpler and resulted in better sparing of critical structures compared with plans based on manual angle selection. The approach provides a practical alternative to elaborate and time consuming beam angle optimization schemes and is suitable for routine clinical usage.

Adenocarcinoma↗

PubMed1994

Economic analysis of investment priorities for measles control.

An investment strategy in measles control should strike an appropriate balance among three areas: implementation of existing vaccination programs with existing technology, operations research to improve the use of existing technology, and vaccine development. As a benchmark, the existing Schwarz vaccine costs approximately $17 per DALY (disability-adjusted life year), already making it one of the most cost-effective health interventions in developing countries. National measles vaccination campaigns, such as Brazil's, are a promising extension of this technology. Operations research is indicated to study the organization of campaigns, supplying and delivering vitamin A to hospitalized children, and other issues. The development and application of an early one-dose measles vaccine would be particularly cost-effective ($5 per DALY), as it could avoid the costs to families and health institutions of the separate visit at 9 months now required for measles vaccination. All three areas present opportunities for cost-effective investments and deserve a place in an investment strategy.

Child, Preschool↗

PubMedDate not supplied

Developmental toxicity of butyl benzyl phthalate in the rat using a multiple dose study design.

The developmental toxicity of butyl benzyl phthalate (BBP) was investigated in the rat using ten dose groups between 270 and 2100 mg/kg/day. Exposure was by daily gavage from gestation day 5 through 16 or gestation day 5 through 20. Dose-response data were analyzed using the benchmark approach by fitting dose-response models to the various endpoints. BBP induced increased liver and kidney weights in dams, accompanied by liver enzyme increases in maternal serum. Extramedullary hematopoiesis, which was already substantial in control pregnant animals, was increased after BBP treatment. Fetotoxicity included increased resorptions, reduced fetal weights, increased incidence of skeletal anomalies, and reduced fetal testis weights in the presence of an increased incidence of retarded testicular descent. As embryotoxicity was found at lower dosages compared to observed maternal toxicity, BBP appeared to be a specifically embryotoxic compound. The extended exposure protocol (gestation day 5 through 20) appeared more sensitive for measuring fetotoxic effects. We recommend the use of more doses in toxicity tests, together with the benchmark approach as an appropriate and more accurate method for analyzing dose-response data compared to the NOAEL approach.

Abnormalities, Drug-Induced↗

PubMed2006

Application of advanced Monte Carlo Methods in numerical dosimetry.

Many tasks in different sectors of dosimetry are very complex and highly sensitive to changes in the radiation field. Often, only the simulation of radiation transport is capable of describing the radiation field completely. Down to sub-cellular dimensions the energy deposition by cascades of secondary electrons is the main pathway for damage induction in matter. A large number of interactions take place until such electrons are slowed down to thermal energies. Also for some problems of photon transport a large number of photon histories need to be processed. Thus the efficient non-analogue Monte Carlo program, AMOS, has been developed for photon and electron transport. Various applications and benchmarks are presented showing its ability. For radiotherapy purposes the radiation field of a brachytherapy source is calculated according to the American Association of Physicists in Medicine Task Group Report 43 (AAPM/TG43). As additional examples, results for the detector efficiency of a high-purity germanium (HPGe) detector and a dose estimation for an X-ray shielding for radiation protection are shown.

Algorithms↗

PubMed2004

Antibiotic use in German university hospitals 1998-2000 (Project INTERUNI-II).

In a pilot study we established a hospital antibiotic use database from which estimates for antibiotic consumption in German hospitals (expressed as defined daily doses per 100 patient days, DDD/100) can be retrieved for both benchmarking and antibiotic use and resistance research purposes. Data from eight university hospitals (1998-2000) showed a mean antibiotic use density of 60.1 DDD/100 in the surgical and 79.3 DDD/100 in the medical services. Antibiotic use was higher in the intensive care units (surgery: 146 DDD/100, medicine: 187 DDD/100) than in haematology-oncology services (110.8 DDD/100) or in other surgical (51.6 DDD/100) and medical (66 DDD/100) service areas. There were major differences in the use of specific antibacterial drug classes between service areas. The established database allows detailed analysis in antibacterial drug use and can be linked to bacterial resistance surveillance databases.

Anti-Bacterial Agents↗

PubMed2004

Altered expression of genes related to zinc homeostasis in early mouse embryos exposed to di-2-ethylhexyl phthalate.

Numerous studies have shown that di-2-ethylhexyl phthalate (DEHP) is teratogenic in animals but the mechanism of developmental toxicity is not well understood. One hypothesis is altered zinc homeostasis. The present study has investigated the effect of DEHP exposure on several key genes in zinc metabolism (MT-I, MT-II, ZnT-1) for early mouse embryos exposed in utero. Time- and dose-dependent effects were examined using expression polymerase chain reaction (PCR) (relative to ACTB) and Western blot analysis of the maternal liver, embryonic brain, and visceral yolk sac at 9 days post-coitus (d.p.c.). Maternal exposure to 800 mg/kg DEHP increased the abundance of MT-I and MT-II transcripts in maternal liver at 3.0, 4.5 and 6.0 h after administration. MT-I and MT-II protein induction was confirmed by Western blot analysis. On the other hand, this exposure down-regulated both transcripts (MT-I, MT-II), as well as transcripts for a zinc transporter (ZnT-1), in the embryonic brain, but not the visceral yolk sac. To examine dose-response relationships, the experiment was repeated for DEHP exposures of 50, 200 and 800 mg/kg. The effect to MT-I and MT-II expression in the maternal liver became significant at the 200 mg/kg dose level. The contrasting effect to MT-I, MT-II and ZnT-1 expression in the embryo was also dose-dependent, and a benchmark computation for the dose resulting in a 5% change in the mean (BMD5) was estimated as 11.6 mg/kg for MT-I, 8.9 mg/kg for MT-II, and 6.6 mg/kg for ZnT-1. We conclude that DEHP exposure to pregnant dams at reasonably low levels during organogenesis stages can alter the expression of several key genes in embryonic zinc homeostasis.

Animals↗

PubMed2006

[Antibiotic consumption between 1996 and 2003: national survey and international comparison].

AIMS: To describe the qualitative and quantitative changes of antibiotic consumption in Hungarian hospitals and in the primary care setting between 1996 and 2003. METHODS: Sales data relating to community and hospital care antibiotic consumption were obtained for the 8 years period of 1996-2003. The 2003 version of the world health organisation (WHO) anatomical therapeutic chemical (ATC)/ defined daily dose (DDD) system was used for calculations and the 2005 version for classifications. The final expression units were DDD/100 bed-days and DDD/1000 inhabitants/day for hospital and community care utilization, respectively. Trend analysis was applied to assess the annual changes in antimicrobial consumption. RESULTS: The total antibiotic consumption in the community setting and in the hospitals remained relatively stable during the study period. The average antibiotic consumption in the community setting (20.20 +/- 1.42 DDD/1000 inhabitants/day was in line with the European average, while the national average hospital antibiotic consumption (24.81 +/- 1.69 DDD/ 100 bed-days) was very low in international benchmark. Changes in the pattern of antibiotic consumption was observed in both settings. Internationally outstanding consumption of penicillins plus beta-lactamase inhibitor combinations (J01CR) and sulphonamides and extremely low utilisation of beta lactamase resistant penicillins (J01CF) were detected. The hospital antibiotic consumption was characterized by extended use of sulphonamides, tetracyclines, and second generation cephalosporins. CONCLUSIONS: The low hospital consumption of antibiotics and the internationally extreme usage of certain antibiotic groups needs further pharmacoepidemiologic analysis.

Ambulatory Care↗

PubMed2006

Quantitative risk analysis of particulate matter in the air: interspecies extrapolation with bioassay and mathematical models.

We analyzed the health risk of particulate matters in the air to humans using bioassay data and a mathematical model. We designed an original dosimetry model to estimate the particle concentration in human respiratory organs, and the concentration of the inhaled particles at the target organ was used for interspecies extrapolation from rat to human. Our model is based on the conventional dosimetry model and deposition model in the previous literature, but clearance parameters have been newly introduced for the simulation of long-term exposure. Lung cancer was set as the risk endpoint in our risk study, and the dose-response relationship at the target organ (lung) was quantitatively analyzed by the benchmark dose (BMD) method. For interspecies extrapolation based on target organ concentration, we assumed benchmark concentration (BMC) related to 1% excess cancer in rats and humans, and the human equivalent concentration (HEC) was searched by back-estimation using our model. The obtained HEC was 948 to 1098 mg/m3, and the unit risk to humans was 9.11 to 10.5 x 10(-9) per 1 microg/m3 of particulate matter. The estimated cancer risk for Japanese people in general was estimated as approximately 9-10 persons per 100,000,000 when the particle concentration in the air is 10 microg/m3.

Air Pollutants↗

PubMed2006

Pediatric susceptibility to 18 industrial chemicals: a comparative analysis of newborn with young animals.

We comprehensively re-analyzed the toxicity data for 18 industrial chemicals from repeated oral exposures in newborn and young rats, which were previously published. Two new toxicity endpoints specific to this comparative analysis were identified, the first, the presumed no observed adverse effect level (pNOAEL) was estimated based on results of both main and dose-finding studies, and the second, the presumed unequivocally toxic level (pUETL) was defined as a clear toxic dose giving similar severity in both newborn and young rats. Based on the analyses of both pNOAEL and pUETL ratios between the different ages, newborn rats demonstrated greater susceptibility (at most 8-fold) to nearly two thirds of these 18 chemicals (mostly phenolic substances), and less or nearly equal sensitivity to the other chemicals. Exceptionally one chemical only showed toxicity in newborn rats. In addition, Benchmark Dose Lower Bound (BMDL) estimates were calculated as an alternative endpoint. Most BMDLs were comparable to their corresponding pNOAELs and the overall correlation coefficient was 0.904. We discussed how our results can be incorporated into chemical risk assessment approaches to protect pediatric health from direct oral exposure to chemicals.

Age Factors↗

PubMed2004

Dose-response modeling and benchmark calculations from spontaneous behavior data on mice neonatally exposed to 2,2',4,4',5-pentabromodiphenyl ether.

In this paper the benchmark dose (BMD) method was introduced for spontaneous behavior data observed in 2-, 5-, and 8-month-old male and female C57Bl mice exposed orally on postnatal day 10 to different doses of 2,2',4,4',5-pentabromodiphenyl ether (PBDE 99). Spontaneous behavior (locomotion, rearing, and total activity) was in the present work quantified in terms of a fractional response defined as the cumulative response after 20 min divided by the cumulative response produced over the whole 1-h test period. The fractional response contains information about the time-response profile (which differs between the treatment groups) and has appropriate statistical characteristics. In the analysis, male and female mice could be characterized by a common dose-response model (i.e., they responded equally to the exposure to PBDE 99). As a primary approach, the BMD was defined as the dose producing a 5 or 10% change in the mean fractional response. According to the Hill model, considering a 10% change the lower bound of the BMD for rearing, locomotion, and total activity was 1.2, 0.85, and 0.31 mg PBDE 99/kg body weight, respectively. A probability-based procedure for BMD modeling was also considered. Using this methodology, the BMD was defined as corresponding to an excess risk of 5 or 10% of falling below cutoff points representing adverse levels of fractional response.

Algorithms↗

PubMed2005

Test of radiation detectors used in homeland security applications.

This work was performed as part of the National Institute of Standards and Technology (NIST) program to support the development of the new American National Standards Institute (ANSI) standards N42.32-2003 and N42.33-2003 for hand-held detectors, and personal electronic dosimeters, as well as to support the Office of Law Enforcement Standards (OLES) and the Department of Homeland Security (DHS) in testing these types of detectors for their use by first responders. These instruments are required to operate over a photon energy range of 60 keV to 1.33 MeV and over a wide range of air-kerma rates. The performance and response of various radiation detectors, purchased by the NIST, was recorded when placed in 60Co, 137Cs, and x-ray beams at different air-kerma rates. The measurements described in this report were performed at the NIST x-ray and gamma-ray radiation calibration facilities. The instruments' response (exposure or dose rate readings) shows strong energy dependence but almost no dependence to different air-kerma rates. The data here reported provide a benchmark in support of current protocols that are being developed for radiation detection instrumentation used in homeland security applications. A future plan is to test these devices, plus other commercially available detectors, against ANSI standards N42.32-2003 and N42.33-2003.

Benchmarking↗

PubMed2005

The 3rd international intercomparison on EPR tooth dosimetry: Part 1, general analysis.

The objective of the 3rd International Intercomparison on Electron Paramagnetic Resonance (EPR) Tooth Dosimetry was the evaluation of laboratories performing tooth enamel dosimetry below 300 mGy. Participants had to reconstruct the absorbed dose in tooth enamel from 11 molars, which were cut into two halves. One half of each tooth was irradiated in a 60Co beam to doses in the ranges of 30-100 mGy (5 samples), 100-300 mGy (5 samples), and 300-900 mGy (1 sample). Fourteen international laboratories participated in this intercomparison programme. A first analysis of the results and an overview of the essential features of methods applied in different laboratories are presented. The relative standard deviation of results of all methods was better than 27% for applied doses in the range of 79-704 mGy. In the analysis of the unirradiated tooth halves 8% of the samples were identified as outliers with additional absorbed dose above background dose.

Benchmarking↗

PubMed2004

Surveillance of antimicrobial use and antimicrobial resistance in intensive care units (SARI): 1. Antimicrobial use in German intensive care units.

OBJECTIVE: To study antimicrobial use for benchmarking and ensuring quality of antimicrobial treatment and to identify risk factors associated with the high use of antimicrobials in German intensive care units (ICUs) through implementation of the SARI (Surveillance of Antimicrobial Use and Antimicrobial Resistance in ICUs) system. DESIGN: Prospective, unit-based surveillance on antimicrobial use from February, 2000, until June, 2002. The data are standardised by use of the defined daily dose (DDD) for each antimicrobial defined by the WHO and by calculating use per 1000 patient days. SETTING: The data were obtained from 35 German ICUs and stratified by type of ICU (medical, surgical, interdisciplinary). RESULTS: To date, the project covers a total of 266,013 patient days in 744 reported ICU months and 354,356 DDDs. Mean antimicrobial use density (AD) was 1,332 DDD/1000 patient days and was correlated with length of stay. Penicillins with beta-lactamase inhibitor (AD 338.3) and quinolones (155.5) were the antimicrobial group with the highest ADs. Comparison with US ICARE (Intensive Care Antimicrobial Resistance Epidemiology)/AUR (Antimicrobial Use and Resistance) data revealed a higher AD for glycopeptides and 3rd generation cephalosporins in ICARE/AUR ICUs, but a higher AD for carbapenems in German SARI ICUs regardless of the type of ICU. In the multivariate analysis, length of stay was an independent risk factor for an AD above the 75% percentile of the total amount of antimicrobials used (OR 1.96 per day); likewise, for the AD above the 75% percentile of carbapenems (OR 1.90 per day) and penicillins with extended spectrum (OR 2.01 per day). High use of glycopeptides and quinolones (AD >75% percentile) correlated with central venous catheter (CVC) rate (OR 1.14 per CVC day per 100 patient days and 1.16, respectively). CONCLUSION: The SARI data on antimicrobials serve ICUs as a benchmark by which to improve the quality of antimicrobial drug administration and for international comparison.

Anti-Bacterial Agents↗

PubMed2003

A systematic benchmark method for analysis and comparison of IMRT treatment planning algorithms.

Tools and procedures for evaluating and comparing different intensity-modulated radiation therapy (IMRT) systems are presented. IMRT is increasingly in demand and there are numerous systems available commercially. These programs introduce significantly different software to dosimetrists and physicists than conventional planning systems, and the options often seem initially overwhelmingly complex to the user. By creating geometric target volumes and critical normal tissues, the characteristics of the algorithms may be investigated, and the influence of the different parameters explored. Overall optimization strategies of the algorithm may be characterized by treating a square target volume (TV) with 2 perpendicular beams, with and without heterogeneities. A half-donut (hemi-annulus) TV with a "donut hole" (central cylinder) critical normal tissue (CNT) on a CT of a simulated quality assurance phantom is suggested as a good geometry to explore the IMRT algorithm parameters. Using this geometry, the order of varying parameters is suggested. First is to determine the effects of the number of stratifications of optimized intensity fluence on the resulting dose distribution, and selecting a fixed number of stratifications for further studies. To characterize the dose distributions, a dose-homogeneity index (DHI) is defined as the ratio of the dose received by 90% of the volume to the minimum dose received by the "hottest" 10% of the volume. The next step is to explore the effects of priority and penalty on both the TV and the CNT. Then, choosing and fixing these parameters, the effects of varying the number of beams can be looked at. As well as evaluating the dose distributions (and DHI), the number of subfields and the number of monitor units required for different numbers of stratifications and beams can be evaluated.

Algorithms↗

PubMed2004

Gene expression profiling reveals multiple toxicity endpoints induced by hepatotoxicants.

Microarray technology continues to gain increased acceptance in the drug development process, particularly at the stage of toxicology and safety assessment. In the current study, microarrays were used to investigate gene expression changes associated with hepatotoxicity, the most commonly reported clinical liability with pharmaceutical agents. Acetaminophen, methotrexate, methapyrilene, furan and phenytoin were used as benchmark compounds capable of inducing specific but different types of hepatotoxicity. The goal of the work was to define gene expression profiles capable of distinguishing the different subtypes of hepatotoxicity. Sprague-Dawley rats were orally dosed with acetaminophen (single dose, 4500 mg/kg for 6, 24 and 72 h), methotrexate (1mg/kg per day for 1, 7 and 14 days), methapyrilene (100mg/kg per day for 3 and 7 days), furan (40 mg/kg per day for 1, 3, 7 and 14 days) or phenytoin (300 mg/kg per day for 14 days). Hepatic gene expression was assessed using toxicology-specific gene arrays containing 684 target genes or expressed sequence tags (ESTs). Principal component analysis (PCA) of gene expression data was able to provide a clear distinction of each compound, suggesting that gene expression data can be used to discern different hepatotoxic agents and toxicity endpoints. Gene expression data were applied to the multiplicity-adjusted permutation test and significantly changed genes were categorized and correlated to hepatotoxic endpoints. Repression of enzymes involved in lipid oxidation (acyl-CoA dehydrogenase, medium chain, enoyl CoA hydratase, very long-chain acyl-CoA synthetase) were associated with microvesicular lipidosis. Likewise, subsets of genes associated with hepatotocellular necrosis, inflammation, hepatitis, bile duct hyperplasia and fibrosis have been identified. The current study illustrates that expression profiling can be used to: (1) distinguish different hepatotoxic endpoints; (2) predict the development of toxic endpoints; and (3) develop hypotheses regarding mechanisms of toxicity.

Animals↗

PubMed2026

Neonatal gene therapy with AAV2/8-LSPhGAA improves hypertrophic cardiomyopathy in the Gaac.1826dupA knock-in murine model.

Pompe disease (PD) results from lysosomal acid α-glucosidase (GAA) deficiency, causing lysosomal glycogen accumulation in cardiac and skeletal muscles. We previously characterized a murine model carrying the orthologous human infantile-onset PD (IOPD) pathogenic variant, c.1826dupA (p.Y609*), introduced into the mouse Gaa gene. Compared to wild-type (WT; C57BL/6NJ) controls, Gaac.1826dupA mice exhibit reduced GAA activity and develop early-onset hypertrophic cardiomyopathy-evidenced by increased left ventricular wall thickness and left ventricular mass index (LVMI)- as well as impaired grip strength and gait abnormalities. To benchmark the model's disease fidelity and assess its responsiveness to established therapeutic intervention, Gaac.1826dupA mice received a single retro-orbital dose of AAV2/8-LSPhGAA (2 × 109 vg/g body weight) at postnatal day 12-14. Twelve weeks post-treatment, mice exhibited supraphysiological GAA enzymatic activity in the heart (550% of WT) and liver (400% of WT) with a 93% reduction in cardiac glycogen. No sex-dependent differences in therapeutic efficacy were observed. Echocardiography revealed robust reversal of cardiac pathology, with wall thicknesses and LVMI values approaching WT levels. In contrast to this profound cardiac rescue, skeletal muscle improvements were modest; while forelimb grip strength remained unchanged, automated gait analysis showed benefit limited to hind paw base of support. These findings demonstrate that the Gaac.1826dupA model mirrors the critical cardiomyopathy characteristic of IOPD. While systemic AAV treatment yields definitive cardiac correction, the partial skeletal muscle response highlights a clear need for optimization. Consequently, the Gaac.1826dupA mouse serves as a high-fidelity platform for evaluating next-generation genomic correction strategies targeting both cardiac and refractory neuromuscular manifestations of PD.

Acid α-glucosidase↗

PubMed2005

Two-week oral toxicity study of 1,4-Dichloro-2-nitrobenzene in rats and mice.

Subacute toxicity of 1,4-dichloro-2-nitrobenzene (DCNB) was examined by feeding F344 rats and BDF1 mice of both sexes a diet containing DCNB at 625, 1250, 2500, 5000 or 10,000 ppm (w/w) for 2 weeks. All DCNB-fed rats survived to the end of the 2-week administration period, but 2 male and 6 female mice fed 10,000 ppm died during this period. The subacute toxicity was characterized by lesions affecting the liver, kidney, testis and hematopoietic system. The liver was the most responsive to DCNB, as evidenced by a dose-related increase in relative liver weight in rats and mice and centrilobular hypertrophy of hepatocytes in mice. An alteration in liver-associated lipid metabolism was suggested from the concomitant increases in serum concentrations of total cholesterol and phospholipid. A lower confidence limit of the benchmark dose yielding the response with 10% extra risk (BMDL10) for the relative liver weight indicated that rats were more responsive to DCNB than mice. The kidney lesion was characterized by alpha2upsilon-globulin-accumulated hyaline droplets in the renal tubular epithelial cells only in male rats, as indicated by positive anti-alpha2upsilon-globulin immunohistochemical staining. Testicular and hematopoietic lesions appeared at higher dose levels than did the liver and kidney lesions.

Administration, Oral↗