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Results for “benchmark dose analysis”

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PubMed2004

Results of a technology demonstration project to compare rapid aquatic toxicity screening tests in the analysis of industrial effluents.

The results of a 'BioWise' demonstration project to assess the comparative sensitivity and practicality of seven new assays for the direct assessment of ecotoxicity in industrial effluents are presented. In addition the aim of the project was to validate the results of the new assays against benchmark data generated from non-proprietary, rapid, microplate screening assays using the regulatory species; freshwater crustacean Daphnia magna and green algae Selenastrum capricornutum, chosen in view of their environmental relevance. The new commercial test assays were: Daphnia magna, Selenastrum capricornutum and Thamnocephalus platyurus Toxkits supplied by Vickers Laboratories Ltd, containing dormant, immobilised life stages of the test species; GreenScreen EM, a yeast based assay for genotoxicity and general acute toxicity supplied by Gentronix Ltd; and CellSense a mediated, amperometric whole cell biosensor based on immobilised activated sludge and E. coli. 38 effluent samples supplied by members of SOCSA (Specialised Organic Chemicals Sector Association) were examined over a period of 13 months, in the project co-ordinated by the AstraZeneca Brixham Environmental Laboratory, and part funded by BioWise via the UK Government Department of Trade and Industry.

Animals↗

PubMed2005

Evaluation of coupled convective-diffusive transport of drugs administered by intravitreal injection and controlled release implant.

A 3-dimensional finite element model was developed to simulate pharmacokinetics in the eye following drug administration by intravitreal injection and implant for the treatment of retinal disease. The contributions of (1) convection to the transport of drug through the vitreous and aqueous humor and (2) diffusion of drug in the vitreous were varied to study the drug elimination from a normal and diseased eye. Drug distribution achieved by intravitreal injection was compared to that for the same dose released at a constant rate over 15 h from an implant. The model was constructed for a rabbit eye and validated with experimental data for intravitreal injection of fluorescein. The implant reduced peak concentration by 43% and increased residence time by 71% for the baseline (6x10(-6) cm2/s drug diffusivity in vitreous and 0.1 microL/min vitreous outflow), when compared with that of intravitreal injection. Therefore, the implant could be beneficial in reducing the peak concentration and sustaining release of the drug for a longer duration. Convection has a relatively small influence in the normal eye for high diffusivity drugs (1x10(-5) cm2/s), but could have a significant effect for low diffusivity drugs (1x10(-7) cm2/s) in pathophysiologically elevated fluid outflow across the retina. By interpolating the results of this benchmark study, one could estimate the distributions for drugs of different molecular weight, and assess the effect of variable vitreous outflows associated with different pathophysiological conditions.

Algorithms↗

PubMed1999

Dosimetric adjustment factors for methyl methacrylate derived from a steady-state analysis of a physiologically based clearance-extraction model.

Cells within the epithelial lining of the nasal cavity metabolize a variety of low-molecular-weight, volatile xenobiotics. In common with terminology developed for other metabolizing organs, the nose extracts these chemicals from the airstream, thereby clearing some portion of the total nasal airflow. In this article, a physiologically based clearance-extraction (PBCE) model of nasal metabolism is used to predict extraction for steady-state conditions. This model, developed by simplification of existing physiologically based pharmacokinetic (PBPK) nasal models, has three tissue regions in two flow paths. A dorsal flow stream sequentially passes over a small area of respiratory epithelium and then over the entire olfactory epithelial surface within the nose. A ventral airstream, consisting of most of the total flow, passes over the larger portion (>80%) of the respiratory epithelium. Each underlying tissue stack has a mucus layer, an epithelial tissue compartment, and a blood exchange region. Metabolism may occur in any of the subcompartments within the tissue stacks. The model, solved directly for a steady-state condition, specifies the volumetric airflow over each stack. Computational fluid dynamic (CFD) solutions for the rat and human for the case with no liquid-phase resistance provided a maximum value for regional extraction, E(max)'. Equivalent air-to-liquid phase permeation coefficients (also referred to as the air-phase mass transfer coefficient) were calculated based on these E(max)' values. The PBCE model was applied to assess expected species differences in nasal extraction and in localized tissue metabolism of methyl methacrylate (MMA) in rats and in humans. Model estimates of tissue dose of MMA metabolites (in micromol metabolized/h/ml tissue) in both species were used to evaluate the dosimetric adjustment factor (DAF) that should be applied in reference concentration (RfC) calculations for MMA. For human ventilation rates equivalent to light exercise, the DAF was estimated to be 3.02 at 28.4 ppm, the benchmark concentration for nasal lesions. Depending on specific assumptions about distribution of esterase activities in human tissues, the range of DAF values was 1.56-8.00. The DAF for heavy exercise with a ventilation rate of 42 L/min was still 2.98. Estimated DAFs were concentration dependent, varying between 2.4 and 4.76 in the inhaled concentration range from 1 and 400 ppm. Present default methods utilize a DAF of 0.145. These steady-state calculations with this PBCE model should be useful in risk assessment calculations for a variety of vapors and gases that are converted to toxic metabolites in cells in the respiratory tract.

Acetates↗

PubMed2001

Reproductive and developmental risks from ethylene oxide: a probabilistic characterization of possible regulatory thresholds.

Ethylene oxide is a gas produced in large quantities in the United States that is used primarily as a chemical intermediate in the production of ethylene glycol, propylene glycol, non-ionic surfactants, ethanolamines, glycol ethers, and other chemicals. It has been well established that ethylene oxide can induce cancer, genetic, reproductive and developmental, and acute health effects in animals. The U.S. Environmental Protection Agency is currently developing both a cancer potency factor and a reference concentration (RfC) for ethylene oxide. This study used the rich database on the reproductive and developmental effects of ethylene oxide to develop a probabilistic characterization of possible regulatory thresholds for ethylene oxide. This analysis was based on the standard regulatory approach for noncancer risk assessment, but involved several innovative elements, such as: (1) the use of advanced statistical methods to account for correlations in developmental outcomes among littermates and allow for simultaneous control of covariates (such as litter size); (2) the application of a probabilistic approach for characterizing the uncertainty in extrapolating the animal results to humans; and (3) the use of a quantitative approach to account for the variation in heterogeneity among the human population. This article presents several classes of results, including: (1) probabilistic characterizations of ED10s for two quantal reproductive outcomes-resorption and fetal death, (2) probabilistic characterizations of one developmental outcome-the dose expected to yield a 5% reduction in fetal (or pup) weight, (3) estimates of the RfCs that would result from using these values in the standard regulatory approach for noncancer risk assessment, and (4) a probabilistic characterization of the level of ethylene oxide exposure that would be expected to yield a 1/1,000 increase in the risk of reproductive or developmental outcomes in exposed human populations.

Animals↗

PubMed2005

Issues in neurological risk assessment for occupational exposures: the Bay Bridge welders.

The goal of occupational risk assessment is often to estimate excess lifetime risk for some disabling or fatal health outcome in relation to a fixed workplace exposure lasting a working lifetime. For sub-chronic or sub-clinical health effects measured as continuous variables, the benchmark dose method can be applied, but poses issues in defining impairment and in specifying acceptable levels of excess risk. Such risks may also exhibit a dose-rate effect and partial reversibility such that effects depend on how the dose is distributed over time. Neurological deficits as measured by a variety of increasingly sensitive neurobehavioral tests represent one such outcome, and the development of a parkinsonian syndrome among welders exposed to manganese fume presents a specific instance. Welders employed in the construction of piers for a new San Francisco-Oakland Bay Bridge in San Francisco were previously evaluated using a broad spectrum of tests. Results for four of those tests (Rey-Osterrieth Complex Figure Test, Working Memory Index, Stroop Color Word Test and Auditory Consonant Trigrams Test) were used in the benchmark dose procedure. Across the four outcomes analyzed, benchmark dose estimates were generally within a factor of 2.0, and decreased as the percentile of normal performance defining impairment increased. Estimated excess prevalence of impairment, defined as performance below the 5th percentile of normal, after 2 years of exposure at the current California standard (0.2 mg/m3, 8 h TWA), ranged 15-32% for the outcomes studied. Because these exposures occurred over a 1-2-year period, generalization to lifetime excess risk requires further consideration of the form of the exposure response and whether short-term responses can be generalized to equivalent 45-year period. These results indicate unacceptable risks at the current OSHA PEL for manganese (5.0 mg/m3, 15 min) and likely at the Cal OSHA PEL as well.

Adult↗

PubMed1997

The variations in long term TLD measurements of environmental background radiation at locations in southeastern New York state and northern New Jersey.

The variations of the measured dose rate in air should be recognized especially where background radiation is used as a comparative benchmark to assess radiation surveillance and environmental remediation work. In this note, the natural variations of the combined gamma and cosmic-ray background air-dose rate as measured by lithium fluoride thermoluminescence dosimeters are reported. The dosimeters were deployed monthly at locations within 150 km of the Environmental Measurements Laboratory in New York City. Urban and suburban stations were established with simultaneous indoor and outdoor measurements at some locations. Measurements were obtained over 10 to 18 years. The mean air-dose rates from the six outdoor and four indoor stations vary from 50.8 to 123.1 nGy h(-1). The range of the annual dose rates expressed as a percent-difference of the minimum and maximum is 5.3 to 18.0%. Commonly, 1-mo deviations from the long term mean of about +/-10 to +/-25% are observed. An abrupt decrease in the annual dose rate at one of the measurement sites was attributed to a minor relocation of a dosimeter. Structural shielding factors for the first and second floors of a residence are reported. The ground level location of a dosimeter inside another residence apparently resulted in a very high shielding factor. Finally, a gradual decrease of the dose rate at most of the stations is shown to exist (approximately -0.3 nGy h(-1) y(-1) for the outdoor stations). Plausible causes of this trend are briefly discussed.

Air Pollution, Indoor↗

PubMed2001

Losartan reduces microalbuminuria in hypertensive microalbuminuric type 2 diabetics.

BACKGROUND: The aim of the present study was to assess the antialbuminuric effect of losartan in a large number of hypertensive type 2 diabetics. METHODS: This was a 6-month, open-label, prospective and multicentre study. A total of 422 patients with type 2 diabetes who were hypertensive [sitting systolic blood pressure (SBP) > or = 140 mmHg and/or diastolic blood pressure (DBP) > or = 90 mmHg] and microalbuminuric [urinary albumin excretion (UAE) 30-300 mg/day] were eligible for the study. After a 2-week run-in period, patients were placed on losartan 50 mg once a day. If the BP did not reach the desired goal (< 140/90 mmHg) after a 4-week period, the losartan dose was doubled. In the absence of control of BP, losartan 50 mg/day+hydroclorothiazide 12.5 mg/day was administrated. Initially and at 12 and 24 weeks of active treatment, BP, UAE, HbA(1c) and other renal function parameters were evaluated. RESULTS: A significant decrease in SBP and DBP was observed, as well as in parameters reflecting metabolic control, fasting glucose and HbA(1c). UAE also decreased significantly, but the percentage of the variance of change in UAE explained by the changes in SBP and HbA(1c) was, however, negligible, i.e. 4%. Moreover, small but significant reductions in uric acid, total cholesterol and triglycerides, and an increase in HDL-cholesterol levels were also observed. CONCLUSION: Antihypertensive treatment with losartan exerts a beneficial effect on UAE, a benchmark for measuring the efficacy of therapeutic interventions in diabetic nephropathy, by reducing BP and allowing better diabetes control. The role of other mechanisms influencing the favourable outcome, beyond these measured effects, needs to be assessed in further studies.

Albuminuria↗

PubMed2003

Process of care and preliminary outcome in limited-stage small-cell lung cancer: results of the 1995-1997 patterns of care study in Japan.

PURPOSE: To evaluate the practice process using the national average (NA); to compare differences in the process of care by age group; and to provide a preliminary outcome data for limited-stage small-cell lung cancer in Japan. METHODS AND MATERIALS: The Patterns of Care Study conducted a nationwide survey of the care process for Stage I-III small-cell lung cancer in Japan. Patients were divided into three age groups: <65 years (younger group, n = 73); between 65 and 74 years (intermediate group, n = 81); and >or=75 years (elderly group, n = 20). RESULTS: The NA for the total dose was 49.0 Gy, and for use of photon energy >or=6 MV, chemotherapy, and prophylactic cranial irradiation was 77.3%, 93.2%, and 1.69%, respectively. Age stratification had no impact on the variables of radiotherapy (RT) such as total dose and field size. Only 37% of patients received chemotherapy and thoracic RT concurrently. The proportion of patients who received chemotherapy and RT concurrently was 44%, 27%, and 25% of the younger, intermediate, and elderly groups, respectively (p = 0.029). Etoposide and cisplatin were less frequently used in the elderly group (>or=75 years old). Overall survival at 3 years for the entire group was 26%. The 3-year survival rate was 30% in the younger group, 28% in the intermediate group, and 9% in the elderly group. Variables found to have a significant impact on survival by multivariate analysis were the use of chemotherapy (p = 0.030), age (p = 0.032), and T stage (p = 0.042). CONCLUSION: Calculated NAs showed that the results of clinical study had favorably penetrated into the practice process in Japan. The results demonstrated that patient age significantly influenced the process of chemotherapy such as the use of etoposide and cisplatin for limited-stage small-cell lung cancer in Japan. More concurrent chemotherapy and thoracic RT and the application of prophylactic cranial irradiation for complete responders need to be investigated in the future.

Age Factors↗

PubMed2003

Documenting pharmacist interventions on an intranet.

The process of developing and implementing an intranet Web site for clinical intervention documentation is described. An inpatient pharmacy department initiated an organizationwide effort to improve documentation of interventions by pharmacists at its seven hospitals to achieve real-time capture of meaningful benchmarking data. Standardization of intervention types would allow the health system to contrast and compare medication use, process improvement, and patient care initiatives among its hospitals. After completing a needs assessment and reviewing current methodologies, a computerized tracking tool was developed in-house and integrated with the organization's intranet. Representatives from all hospitals agreed on content and functionality requirements for the Web site. The site was completed and activated in February 2002. Before this Web site was established, the most documented intervention types were Renal Adjustment and Clarify Dose, with a daily average of four and three, respectively. After site activation, daily averages for Renal Adjustment remained unchanged, but Clarify Dose is now documented nine times per day. Drug Information and i.v.-to-p.o. intervention types, which previously averaged less than one intervention per day, are now documented an average of four times daily. Approximately 91% of staff pharmacists are using this site. Future plans for this site include enhanced accessibility to the site with wireless personal digital assistants. The design and implementation of an intranet Web site to document pharmacists' interventions doubled the rate of intervention documentation and standardized the intervention types among hospitals in the health system.

California↗

PubMed2006

The fast halo assay: an improved method to quantify genomic DNA strand breakage at the single-cell level.

The present study describes the improvement of a technique, the alkaline-halo assay (AHA), for the assessment of DNA single-strand breakage at the single-cell level. AHA involves a series of sequential steps in which cells are embedded in melted agarose and spread onto microscope slides, incubated in a high-salt alkaline lysis solution, then in a hypotonic alkaline solution and, finally, stained with ethidium bromide (EB). Under these conditions, single-stranded DNA fragments diffuse radially from the nuclear cage and generate a fluorescent image that resembles a halo concentric to the nuclear remnants: the area of the halo is a direct function of the extent of DNA strand scission. These phenomena can be conveniently monitored with a fluorescence microscope and quantified by image-processing analysis. The behaviour of single-stranded DNA fragments under the conditions of the modified assay, called fast halo assay (FHA), is essentially the same as in AHA. The modifications consist in the simplification of the lysis, denaturation and staining procedures, and allow, as compared with AHA, the preparation of samples within 15 min, with a two-third reduction in total processing time, using only two reagents to promote DNA extraction and staining: NaOH and EB. A variation of the FHA operating at non-denaturing conditions to discriminate apoptotic cells from non-apoptotic cells bearing DNA single-strand breaks is also illustrated. To benchmark FHA sensitivity and reliability, the DNA single-strand breaks (SSBs) resulting either from exposure of cultured mammalian cells to different DNA-damaging agents or from secondary apoptotic DNA cleavage, have been quantified and results compared with the outcomes of reference techniques run in parallel, namely AHA, comet assay and Hoechst 33342 staining. The results indicate that FHA has the same reliability and sensitivity of the reference assays, but presents the additional advantages of being inexpensive, more rapid and strikingly simple.

Alkalies↗

PubMed2006

Accuracy of patient dose calculation for lung IMRT: A comparison of Monte Carlo, convolution/superposition, and pencil beam computations.

The accuracy of dose computation within the lungs depends strongly on the performance of the calculation algorithm in regions of electronic disequilibrium that arise near tissue inhomogeneities with large density variations. There is a lack of data evaluating the performance of highly developed analytical dose calculation algorithms compared to Monte Carlo computations in a clinical setting. We compared full Monte Carlo calculations (performed by our Monte Carlo dose engine MCDE) with two different commercial convolution/superposition (CS) implementations (Pinnacle-CS and Helax-TMS's collapsed cone model Helax-CC) and one pencil beam algorithm (Helax-TMS's pencil beam model Helax-PB) for 10 intensity modulated radiation therapy (IMRT) lung cancer patients. Treatment plans were created for two photon beam qualities (6 and 18 MV). For each dose calculation algorithm, patient, and beam quality, the following set of clinically relevant dose-volume values was reported: (i) minimal, median, and maximal dose (Dmin, D50, and Dmax) for the gross tumor and planning target volumes (GTV and PTV); (ii) the volume of the lungs (excluding the GTV) receiving at least 20 and 30 Gy (V20 and V30) and the mean lung dose; (iii) the 33rd percentile dose (D33) and Dmax delivered to the heart and the expanded esophagus; and (iv) Dmax for the expanded spinal cord. Statistical analysis was performed by means of one-way analysis of variance for repeated measurements and Tukey pairwise comparison of means. Pinnacle-CS showed an excellent agreement with MCDE within the target structures, whereas the best correspondence for the organs at risk (OARs) was found between Helax-CC and MCDE. Results from Helax-PB were unsatisfying for both targets and OARs. Additionally, individual patient results were analyzed. Within the target structures, deviations above 5% were found in one patient for the comparison of MCDE and Helax-CC, while all differences between MCDE and Pinnacle-CS were below 5%. For both Pinnacle-CS and Helax-CC, deviations from MCDE above 5% were found within the OARs: within the lungs for two (6 MV) and six (18 MV) patients for Pinnacle-CS, and within other OARs for two patients for Helax-CC (for Dmax of the heart and D33 of the expanded esophagus) but only for 6 MV. For one patient, all four algorithms were used to recompute the dose after replacing all computed tomography voxels within the patient's skin contour by water. This made all differences above 5% between MCDE and the other dose calculation algorithms disappear. Thus, the observed deviations mainly arose from differences in particle transport modeling within the lungs, and the commissioning of the algorithms was adequately performed (or the commissioning was less important for this type of treatment). In conclusion, not one pair of the dose calculation algorithms we investigated could provide results that were consistent within 5% for all 10 patients for the set of clinically relevant dose-volume indices studied. As the results from both CS algorithms differed significantly, care should be taken when evaluating treatment plans as the choice of dose calculation algorithm may influence clinical results. Full Monte Carlo provides a great benchmarking tool for evaluating the performance of other algorithms for patient dose computations.

Algorithms↗

PubMed2003

Monte Carlo model of the Elekta SLiplus accelerator: validation of a new MLC component module in BEAM for a 6 MV beam.

A new component module (CM), called MLCE, has been implemented in the BEAM program. The CM takes into account the particular 'tongue-and-groove' design of the Elekta multi-leaf collimator (MLC) and the air gap between the leaves. The model was validated by two series of measurements and simulations. The first benchmarking series focuses on the interleaf leakage and the intraleaf transmission. The measurement showed a total transmission through the MLC of 1.42% of the open field dose. Two Monte Carlo (MC) simulations were made, the first with the new CM MLCE (inclusive of air gap) and the second with the CM MLCQ (exclusive of air gap), which is available in the BEAM distribution. When the air gap between the leaves was determined by varying the parameters of the leaf geometry within tolerance limits on the technical drawing, the total measured transmission of 1.42% was well reproduced by the CM MLCE. In contrast, MC simulations with MLCQ showed that the transmission through the MLC calculated without the interleaf leakage is only 44% of the total transmitted radiation. The relevance of the detailed MLC modelling was demonstrated also by studying the 'adjacent' tongue-and-groove effect, where two adjacent (not opposing) leaves are complementary, opened or closed. The two complementary leaf settings were simulated both with the CM MLCE and MLCQ. A comparison with measurements was made. In regions covered by two or more leaves, the dose increased by 14% for two leaves and by 40% for more than two leaves when the interleaf leakage was included in the transmission. The tongue-and-groove effect was perfectly reproduced by the MLCE module.

Algorithms↗

PubMed2003

Scattered radiation from applicators in clinical electron beams.

In radiotherapy with high-energy (4-25 MeV) electron beams, scattered radiation from the electron applicator influences the dose distribution in the patient. In most currently available treatment planning systems for radiotherapy this component is not explicitly included and handled only by a slight change of the intensity of the primary beam. The scattered radiation from an applicator changes with the field size and distance from the applicator. The amount of scattered radiation is dependent on the applicator design and on the formation of the electron beam in the treatment head. Electron applicators currently applied in most treatment machines are essentially a set of diaphragms, but still do produce scattered radiation. This paper investigates the present level of scattered dose from electron applicators, and as such provides an extensive set of measured data. The data provided could for instance serve as example input data or benchmark data for advanced treatment planning algorithms which employ a parametrized initial phase space to characterize the clinical electron beam. Central axis depth dose curves of the electron beams have been measured with and without applicators in place, for various applicator sizes and energies, for a Siemens Primus, a Varian 2300 C/D and an Elekta SLi accelerator. Scattered radiation generated by the applicator has been found by subtraction of the central axis depth dose curves, obtained with and without applicator. Scattered radiation from Siemens, Varian and Elekta electron applicators is still significant and cannot be neglected in advanced treatment planning. Scattered radiation at the surface of a water phantom can be as high as 12%. Scattered radiation decreases almost linearly with depth. Scattered radiation from Varian applicators shows clear dependence on beam energy. The Elekta applicators produce less scattered radiation than those of Varian and Siemens, but feature a higher effective angular variance. The scattered radiation decreases somewhat with increasing field size and is spread uniformly over the aperture. Experimental results comply with the results of simulations of the treatment head and electron applicator, using the BEAM Monte Carlo code, and Siemens, but feature a higher effective angular variance. The scattered radiation decreases somewhat with increasing field size and is spread uniformly over the aperture. Experimental results comply with the results of simulations of the treatment head and electron applicator, using the BEAM Monte Carlo code.

Algorithms↗

PubMed1994

A benchmark of cell survival models using survival curves for human cells after completion of repair of potentially lethal damage.

Six models of radiation action (the linear-quadratic model, the multitarget model with initial slope, the repair-misrepair model, the lethal-potentially lethal model, the cybernetic model, the saturable repair model) were tested for their goodness of fit to survival curves for human cells. Fifty-three survival curves for human cells irradiated in plateau phase and after completion of repair of potentially lethal damage (PLD) provided the experimental basis for the tests. Three criteria were considered. The capacity to describe the survival data was estimated, using the error left unexplained by the model. A validation of models was achieved by consideration of the mean residual squared errors. The ability of the parameters to characterize survival curves was investigated, studying their variation within and among curves. The models were not equivalent, whatever the test. The saturable repair model and the multitarget with initial slope model gave the most accurate description of survival data. The linear-quadratic model had the most reliable parameters, so that comparisons of the cell survival curves could be made advantageously. The cybernetic model and the lethal-potentially lethal model were found inappropriate for the analysis of survival curves for human cells after completion of PLD repair.

Analysis of Variance↗

PubMed1997

Estimating benchmark concentrations and other noncancer endpoints in epidemiology studies.

Methods for evaluating the hazards associated with noncancer responses with epidemiologic data are considered. The methods for noncancer risk assessment have largely been developed for experimental data, and are not always suitable for the more complex structure of epidemiologic data. In epidemiology, the measurement of the response and the exposure is often either continuous or dichotomous. For a continuous noncancer response modeled with multiple regression, a variety of endpoints may be examined: (1) the concentration associated with absolute or relative decrements in response; (2) a threshold concentration associated with no change in response; and (3) the concentration associated with a particular added risk of impairment. For a dichotomous noncancer response modeled with logistic regression, concentrations associated with specified added/extra risk or with a threshold responses may be estimated. No-observed-effect concentrations may also be estimated for categorizations of exposures for both continuous and dichotomous responses but these may depend on the arbitrary categories chosen. Respiratory function in miners exposed to coal dust is used to illustrate these methods.

Age Factors↗

PubMed2003

Benchmark calculations in risk assessment using continuous dose-response information: the influence of variance and the determination of a cut-off value.

A benchmark dose (BMD) is the dose of a chemical that corresponds to a predetermined increase in the response (the benchmark response, BMR) of a health effect. In this article, a method (the hybrid approach) for benchmark calculations from continuous dose-response information is investigated. In the formulation of the methodology, a cut-off value for an adverse health effect has to be determined. It is shown that the influence of variance on the hybrid model depends on the choice of determination of the cut-off point. If the cut-off value is determined as corresponding to a specified tail proportion of the control distribution, P(0), the BMD becomes biased upward when the variance is biased upward. On the contrary, if the cut-off value is directly determined to some level of the continuous response variable, the BMD becomes biased upward when the variance is biased downward. A simulation study was also performed in which the accuracy and precision of the BMD was compared for the two ways of determining the cut-off value. In general, considering BMRs of 1, 5, and 10% (additional risk) the precision of the BMD became higher when the cut-off value was estimated by specifying P(0), relative to the case with a direct determination. Use of the square-root of the maximum-likelihood estimator of the variance in BMD estimation may provide a bias that is reflected by the cut-off formulation (downward bias if specifying P(0), and upward bias if specifying the cut-off, c, directly). This feature may be reduced if an unbiased estimator of the standard deviation is used in the calculations.

Analysis of Variance↗

PubMed1998

Procedures for calculating benchmark doses for health risk assessment.

Safety assessment for noncancer health effects generally has been based upon dividing a no observed adverse effect (NOAEL) by uncertainty (safety) factors to provide an acceptable daily intake (ADI) or reference dose (RfD). Since the NOAEL does not utilize all of the available dose-response data, allows higher ADI from poorer experiments, and may have an unknown, unacceptable level of risk, the benchmark dose (BD) with a specified, controlled low level of risk has become popular as an adjunct to the NOAEL or the low observed adverse effect level (LOAEL) in the safety assessment process. The purpose of this paper is to summarize statistical procedures available for calculating BDs and their confidence limits for noncancer endpoints. Procedures are presented and illustrated for quantal (binary), quasicontinuous (proportion), and continuous data. Quasicontinuous data arise in developmental studies where the measure of an effect for a fetus is quantal (normal or abnormal) but the experimental unit is the mother (litter) so that results can be expressed as the proportion of abnormal fetuses per litter. However, the correlation of effects among fetuses within a litter poses some additional statistical problems. Also, developmental studies usually include some continuous measures, such as fetal body weight or length. With continuous data there generally is not a clear demarcation between normal and adverse measurements. In such cases, extremely high and/or low measurements at some designated percentile(s) can be considered abnormal. Then the probability (risk) of abnormal individuals can be estimated as a function of dose. The procedure for estimating a BD with continuous data is illustrated using neurotoxicity data. When multiple measures of adverse effects are available, a BD can be estimated based on a selected endpoint or the appearance of any combination of endpoints. Multivariate procedures are illustrated using developmental and reproductive toxicity data.

Animals↗

PubMed2006

Prostate HDR radiation therapy: a comparative study evaluating the effectiveness of pain management with peripheral PCA vs. PCEA.

INTRODUCTION: High dose rate (HDR) brachytherapy is considered one of the most advanced treatment technologies currently available for treatment of localized prostate cancer. It gives the advantage of applying higher dose radiation, with greater precision, directly to the tumor while sparing healthy tissue and surrounding organs, thereby resulting in fewer side effects. In this facility, the treatment requires an overnight stay in the hospital, in a supine position, with a perineal template sutured to the perineum to prevent catheter movement or dislodgement. PURPOSE: To compare the effectiveness of pain management for men with prostate cancer being treated with HDR brachytherapy using a peripheral patient controlled analgesia (PCA) or patient controlled epidural analgesia (PCEA). METHOD: A comparative study was conducted evaluating the effectiveness of two pain management methods for men with prostate cancer receiving HDR brachytherapy. Pain assesments were conducted by scoring pain from the Foley catheter, interstitial catheter (perineal) and back (lumbosacral), using the Brief Pain Inventory Scale. RESULTS: Patients receiving pain management with the PCEA experienced significantly less pain. CONCLUSIONS: These finding suggest that use of PCEA with bupivacaine and fentanyl is more effective in managing pain related to HDR brachytherapy for prostate cancer, and results in a positive patient outcome thereby improving patient satisfaction.

Analgesia, Epidural↗