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Results for “benchmark dose analysis”

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PubMed1999

CT-based dosimetry calculations for 125I prostate implants.

PURPOSE: To evaluate the Monte Carlo code MCNP4B for low-energy brachytherapy calculations, including the effects of interseed attenuation and patient specific heterogeneities, on the calculated dose distribution from transperineal implantation of 125I. METHODS AND MATERIALS: The Monte Carlo code MCNP4B was used to model and benchmark the absolute dose distribution from two 125I brachytherapy seeds (model 6711 and 6702). Based upon the physical source model, the total photon intensity and differential energy spectrum were evaluated as a function of angle from the transverse bisector of the source. These spectral and intensity data were reformatted to produce probability distributions for sampling from a virtual point source. The virtual source model and a modified version of MCNP4B is then used for simulating arbitrary brachytherapy source configurations within a homogeneous or heterogeneous patient specific computed tomography (CT)-based lattice geometry. RESULTS AND CONCLUSION: Comparison with TG-43 data and the Monte Carlo calculations is excellent with MCNP4B predicting the radial dose function for the 125I 6711 and 6702 sources within 6% for all data points tested. Attenuation effects from neighboring seeds were investigated for pre- and postimplant seed distributions and found to be negligible. Preliminary dosimetry analysis of postimplant seed distributions comparing homogeneous water versus heterogeneous CT simulation geometries indicates an average decrease of approximately 5.6% for the volume of tissue irradiated to a prescription isodose line of 144 Gy.

Brachytherapy↗

PubMed1999

Osteolymphoma (primary bone lymphoma): an Australian review of 70 cases. Australasian Radiation Oncology Lymphoma Group (AROLG).

BACKGROUND: To examine prognostic factors, treatment outcomes and design future studies for Osteolymphoma (OL)--also known as primary bone lymphoma. METHODS: Between 1979 and 1993, 70 patients with OL were treated in nine Australian centres. The effect of patient-, tumour-, and treatment-related factors on local control, distant disease-free survival and overall survival were assessed by multivariate analysis. RESULTS: Most patients (94%) received radiotherapy (RT) (median dose 40 Gy) and 56% received chemotherapy. Multifocal disease was present in 20% of patients. The five year rates of overall survival and local control were 59% and 82%. Although there was a trend towards better results with the addition of chemotherapy, on multivariate analysis, there were no factors identified which appeared to impact upon overall and disease-free survival. Among the distant recurrences, there was a high proportion in bone (33%). Six patients suffered pathological fractures after treatment. CONCLUSION: High rates of local control were achieved by RT, but the overall survival remains relatively poor, worse than nodal lymphoma. The natural history of the disease suggests that OL may be a distinct entity, different to nodal lymphomas, so the results of clinical trials in nodal lymphoma may not be relevant to OL. Prospective studies could define the outcome of combined modality therapy and set a benchmark for testing further proposals, as well as improving our knowledge of the clinical features of OL.

Adult↗

PubMed1999

Calculating photon beam characteristics with Monte Carlo techniques.

This study describes the results from a simulation of a 10 MV photon beam from a medical linac using the BEAM code. To check the quality of the generated photon beam, the characteristics of this beam (depth dose curve, cross profiles, and output factors) have been calculated and compared to measured data. By splitting up the radiation head in two parts, the target section and the collimator section calculation times were long, but acceptable when aiming at phase space files containing some 5 million particles. Given the number of particles evaluated, the accuracy of all data was around 2%. Analysis of the phase space files for different field size supports results from previous studies about contaminant particles and sources for scattered radiation for photon beams from medical linacs. The total scatter output factor Scp as well as the collimator scatter output factor Sc have been calculated within 2% of measurements. Also, the ratio between dose at a reference point for the full scatter situation and the no-scatter situation has been calculated correctly. All depth dose curves and cross profiles have also been calculated correctly, although with only moderate statistics. Improvements are possible by increasing the number of particles in the simulations (up to 50 million for the largest field size) at least 4-8 times, although calculation times will increase with the same factor. Nevertheless, the method proved itself as reliable. Still, the accuracy should be improved to 1% or better. This is necessary as we plan to use Monte Carlo simulations to benchmark three-dimensional radiotherapy planning systems. By increasing the number of particles in the phase space files and subsequently increasing the number of particles in each simulation, this 1% accuracy will be achieved. The easy way to increase the number of particles in a simulation by increasing the number of times phase space files, which were already recycled ten times, are reused from ten times (this study) to 40 times or more will not work, as it introduces artifacts, especially in the cross profiles.

Biophysical Phenomena↗

PubMed2002

Performance characteristics of the Pantak Therapax-150 superficial X-ray treatment machine: measurements and calculations.

The beam and operating performance characteristics of a superficial X-ray unit, the Pantak Therapax-150 have been evaluated and benchmarked against the Monte Carlo code-MCNP. Parameters which were studied included beam quality, central axis depth dose and field uniformity for several applicator sizes and focal skin distances (FSDs) with the tube operating between 50 and 150 kVp accelerating potential. MCNP calculations were compared with five published qualities: 3.75 mm Al, 3.27 mm Al, 2.43 mm Al, 7.15 mm Al and 1.65 mm Cu half value layer (HVL). The unit has been found to provide beam characteristics similar to those reported for other superficial therapy machines. For most of the combinations of radiation qualities and applicators, good agreement between experiments an dcalculations was obtained. Calculated data when compared with other workers was not worse than 8.8%.

Equipment Failure Analysis↗

PubMed1995

The United States Renal Data System: a source of national norms for ESRD patient outcome and process of care.

The Annual Data Report of the United States Renal Data System provides a rich resource of published summaries of the United States norms for end-stage renal disease (ESRD) patient outcome and process of care. It includes summaries of patient mortality rates, hospitalization rates, causes of death, and rates of withdrawal from dialysis based on a near-census of ESRD patients in the United States. Norms for some measures of the process of delivering dialysis therapy, including dose of dialysis are also reported, based on a national random sample of ESRD patients. National summaries of measures of patient outcome and process of care provide a useful benchmark against which specific experience can be compared. Such comparisons can be part of a quality improvement program that encourages caregivers to provide high quality care to ESRD patients. While the Annual Data Report provides summaries of several fundamental measures related to high quality care, including patient survival and quality of life, other measures need to be developed and studied, including more direct measures of quality of life.

Cause of Death↗

PubMed1996

A benchmark concentration for carbon disulfide: analysis of the NIOSH carbon disulfide exposure database.

A statistical analysis of the NIOSH (National Institute for Occupational Safety and Health) carbon disulfide (CS2) exposure database was conducted for purposes of establishing a benchmark concentration (BMC) for CS2. The analysis addressed the effects of CS2 exposure on the peripheral nervous system and on ischemic heart disease risk factors. The BMC is based on models relating response to exposure determined from statistical analysis of the continuous exposure data for individuals recorded in the NIOSH database. The results demonstrate that changes in the responses associated with increases in CS2 exposure at levels represented in the NIOSH database are relatively small after adjustment for confounders. The only response variables that had statistically significant relationships with CS2 were the peroneal nerve MCV (motor conduction velocity) and the peroneal nerve amplitude ratio. Based on these results, BMCs of 16.2 and 18.5 ppm were derived for MCV and amplitude ratio, respectively.

Carbon Disulfide↗

PubMed2000

Can benchmarking be applied to radiation protection? And is it useful?

PURPOSE: Any program of protection from the ionizing radiations used for health care must ultimately lead to the total prevention of graduated effects and to the limitation of probabilistic effects to acceptable levels. The latter are the more dangerous because they may occur even at very low doses and involve the whole population including unexposed subjects; these effects may appear in the generations to come. The specific protection of the health of operators, patients, and the general population, depends on a series of physical-technical and bureaucratic-administrative factors. These must be known and applied based on precise reference standards, recommended or stated by law, as well as on appropriately regulated and controlled procedures. We chose to apply the benchmarking method to radiation protection in order to standardize and increase the efficacy of prevention and to plan, according to Deming's cycle, the continuous improvement of radiation protection performance. METHOD: Benchmarking is a qualitative intercomparison method widely used in business economics to improve performance referring to best practice and the best in class. When applied in a department where all the partners belong (internal benchmarking), the method features a subdivision into different (sub)processes integrated according to the logic of problem-solving. These stages are: planning: 1) identifying benchmarking issues; 2) identifying the participants; 3) deciding the data collection method; 4) data collection; analysis: 5) measuring the gap; 6) planning future performance; integration: 7) reporting the results; 8) setting the functional goals; action: 9) developing and implementing plans; 10) checking results and resetting the target. The gross subdivision of resources into human and structural permits to check the gap between an actual and an ideal setting separately. Thus, the procedures will give information on the human factor which will be periodically checked in loco relative to all active and passive conducts, while standards will be used to assess the available spaces, facilities and equipment, as well as the relative regular activity. Specific physical-technical and bureaucratic-administrative indices will be needed in both cases. RESULTS AND DISCUSSION: Solving the operators' doubts and consequently decreasing the statistical errors and/or the cases of incorrect performance has resulted in improved rendered quality, which will be further increased after the planned replacement of substandard or unsafe equipment. Meanwhile, the early application of equipment quality controls has helped rationalize and markedly decrease maintenance costs, which results in possible technologic investment to improve emergency imaging. Greater attention to their protection has made patients feel an improvement in received quality and has increased empathy in general. Total quality, as compared with the best practice, has increased thanks to the positive stimulus from standardization, emulation and sharing, and not only to the controls performed. It is difficult to evaluate the management indices, especially the performance efficacy, that is the relationship between radiation protection and results, because the work is in progress and we still lack the actual data on the decrease in accidents at work or occupational diseases of the operators. Moreover, the epidemiological data on radiation-induced conditions will be difficult to collect and interpret, which will make the dynamics of lawsuits for unwarranted or excessive exposure a useful and more readily available piece of information. Finally, relative to economic results, we would like to stress that no additional costs have been necessary to implement safety and quality in a setting involving, directly or indirectly, thousands of people. (ABSTRACT TRUNCATED)

Algorithms↗

PubMed2002

Pollutants in house dust as indicators of indoor contamination.

This review summarizes occurrence of organic and inorganic contaminants in house dust and the contribution of house dust as a marker of indoor exposure. Several studies have identified house dust as an important route of toxicant exposure. Often levels of pollutants found in house dust, including compounds banned long ago, are significant sources of exposure for the general population, especially children. House dust is a sink and repository for semivolatile organic compounds and particle-bound matter. Analyses of compounds in house dust are a measure of indoor contamination but may also provide valuable information for assessment of human indoor exposure. The objective of analyzing house dust are to describe the extent, distribution, and determinants of exposure, to identify possible sources of indoor contamination, or to record elevated indoor exposure leading to intervention or sanitation. House dust and compounds adsorbed to house dust may enter the human body by inhalation of suspended and resuspended particles, through nondietary ingestion of dust, through ingestion of particles adhering to food, surfaces in the homes, and on the skin as well as by absorption through the skin. The quantity of dust inhaled and deposited in the differing parts of the alveolar tract is dependent on the aerodynamic diameter. Exposure to house dust does not exclusively and may not even predominantly occur via inhalation, however. For instance, ingestion of house dust particles adhering to food, objects, and the skin or direct absorption through the skin may be primary routes of exposure (Lewis et al. 1994). Samples referred to as "house dust" vary significantly because house dust may be of different origin, amount, and composition and the method of sampling the dust influences the properties of the sample used for analysis. Passive and active sampling methods are described and discussed. For the analysis of organic pollutants in house dust, the < or = 63-microns fraction should be favored because variances caused by inhomogeneity of the subsample are low. Results from studies on house dust are presented for polychlorinated biphenyls (PCB), polycyclic aromatic hydrocarbons (PAH), plasticizers (phthalates, phenols), flame retardants, other organic xenobiotics, and inorganic constituents. If available, medians as a measure of the average concentration and the 90th or 95th percentiles are added as reference values. The review of the literature points out that ingestion of house dust may be a major route of exposure to pesticides for infants and toddlers. So far, only a few guideline values or limiting values for house dust exist. For lead in house dust, the health risk is regulated only in the U.S. and for PAH in the Federal Republic of Germany. Risk associated with the ingestion of contaminated dust by small children (age, 1-6 years; mean body weight, 16 kg) can be estimated using the chronic oral reference dose (RfD) and a daily intake of 100 mg house dust. The tentative benchmark house dust concentrations that are believed to be without health effect for small children were calculated for several compounds from their current RfD. Comparison with the maximum concentrations reviewed for chlorpyrifos, DDT, and diazinon indicates that the tolerable exposure concentration in house dust might be exceeded and that chlorpyrifos especially can be considered as a potential hazard to householders. The role of house dust as an exposure source is gaining more attention over the years but several open questions related to health remain to be resolved. Pesticides applied outside or within the household that are absorbed and preserved by house dust can lead through the everyday activities of children and infants to increased exposure. Residential exposure including house dust residues contribute to combined exposure from dietary and nondietary sources. It is justified to shift more attention to indoor pollution by house dust contamination and to improve the risk assessment of nondietary ingestion, but any health-based standard must be accompanied by a specific dust sampling method.

Air Pollutants↗

PubMed1980

A simple work measurement system that can aid in effective production planning.

With the advent of increased controls in the hospital field has come the mandate for more efficient use of available resources. Production planning is the mechanism by which these efficiencies can be gained. Ongoing measurement of various work components must be conducted and retrospectively compared to make meaningful use of production planning techniques. The pharmacy department at Brokaw Hospital, which utilizes a unit dose drug distribution system combined with intravenous admixture and monitoring services, has developed an internal measurement system based on key variable weighted units of service. Each component is assigned a value depending on time needed (in minutes) for completion. The units are tabulated daily, with the monthly sum being divided by departmental manhours to yield a monthly productivity ratio. This ratio is used as an aid in making decisions related to work assignments and staff scheduling. Compared against the productivity ratio of a benchmark month of known departmental efficiency (derived by measuring all activities for the month divided by man-hours consumed), projections can be made for future manpower requirements.

Efficiency↗

PubMed2004

Standard fields of old neutron sources--parameters and traceability.

Standard neutron fields of isotope neutron sources, established in the Institute of Atomic Energy, Poland, have been examined for nearly 20 y. The neutron dose equivalent and gamma dose rates were measured, applying various techniques. The neutron emission of standard neutron sources of 241Am-Be and 252Cf has been originally determined in primary standard laboratory, then checked, making use of transfer instrument calibrated in primary laboratory. The growth of neutron emission of 239Pu-Be source, used for routine calibrations, has been demonstrated. The total uncertainty of determined parameters has been discussed. The periodically repeated checks of neutron fields of standard sources with the use of transfer instrument, calibrated in primary laboratory, should provide the traceability to primary laboratory and the fields could be officially recognised.

Benchmarking↗

PubMed2006

A regression spline model for developmental toxicity data.

Observed dose-response patterns of data from several developmental toxicity experiments appear to be nonlinear and should be characterized by an appropriate model to adequately fit this observed pattern. Information from these animal studies of ambient substances that are noncarcinogenic, yet potentially toxic, to humans is used by federal protection agencies (Environmental Protection Agency, Occupational Safety and Health Administration, Food and Drug Administration) to determine safe exposure levels, such as no observed adverse effects level and benchmark dose. We have developed a flexible regression linear B-spline model for application to developmental toxicity dose-response data from animal studies of these noncarcinogens. We apply our model to data from two CD-1 mice studies of the National Toxicology Program; the observed dose-response pattern from both appears nonlinear: (1) experiment of 131 pregnant mice allocated over five exposure levels (0, 0.025, 0.05, 0.10, and 0.15% diet) of diethylhexyl phthalate and (2) experiment of 111 pregnant mice exposed to five levels (0, 62.5, 125, 250, and 500 mg/kg/day) of diethylene glycol dimethyl ether. In each study, we measure litter response as the proportion of adversely affected fetuses. Upon applying our B-spline model to the data from both studies, we predict nonlinear dose-response, with improvement over the more typical logistic dose-response model in each of the two studies.

Animals↗

PubMed2004

Reference dose for perchlorate based on thyroid hormone change in pregnant women as the critical effect.

The most relevant data for developing a reference dose (RfD) for perchlorate exposures comes from human epidemiology and clinical studies, supplemented with available and extensive information on experimental animals. Specifically, serum T4 decrease is the critical effect of perchlorate, based on a mode-of-action analysis and the evidence provided by the body of rodent studies on perchlorate. However, no T4 decreases have been observed in human populations following perchlorate exposure at non-therapeutic doses. An RfD of 0.002 mg/kg-day can be derived using an epidemiology study. A freestanding NOAEL of 0.006 mg/kg-day for T4 decrease was identified in children from the epidemiology study. The use of this NOAEL has the advantage of a being identified in a sensitive subgroup, neonates and children. Data are sufficient to estimate an overall uncertainty factor of 3-fold with this NOAEL based on expected differences in toxicokinetics and toxicodynamics between children, and pregnant women and their fetuses, the second identified sensitive subgroup for perchlorate, and concerns about the over-iodination of this population. This RfD is supported by a human clinical study using inhibition of iodine uptake in adults as a measurable surrogate for the critical effect of T4 decrease in humans. However, although this latter study has a well-established dose-response curve for inhibition of iodine uptake, even perchlorate doses that result in a 70% inhibition of iodine uptake have no apparent effect on human T4 levels. Thus, the use of this study as the primary basis of the RfD is problematic. Nevertheless, a benchmark dose of 0.01 mg/kg-day was identified in this clinical study, which supports a threshold value of 0.006 mg/kg-day identified by its authors and the RfD of 0.002 mg/kg-day estimated in this paper.

Administration, Oral↗

PubMed2003

External quality assessment for warfarin dosing using computerised decision support software.

AIM: To establish and evaluate an external quality assessment scheme for warfarin dosing for users of a computerised decision support system, BAP-PC. DESIGN: Analysis of 12 months of clinical data from 10 primary care centres using BAP-PC within an oral anticoagulation clinic. Data were analysed for individual centres and compared with aggregated data for all practices. Individual feedback forms were provided to participating centres. RESULTS: A total patient population of 367 (range, 17-65/centre) was analysed. On average, patients spent 69% of time in the therapeutic range (range, 60-76%). Patients were seen on average every 27 days (range, 24-30). The average point prevalence was 86% (range, 76-100%). In total, 33 adverse events were reported (0-13/practice). Serious adverse events ranged from 0 to 1 for each practice. This translates into a serious adverse event rate of 1.6/100 patient years. CONCLUSIONS: Practices were successful in maintaining good therapeutic international normalised ratio control, with centres achieving 60% or higher time in range. There are some doubts about the quality of data collection at a practice level because there were no reported events in half of the participating centres. The observed event rates do concur with previously reported data, however. Further cycles of the scheme are necessary to establish it as a useful research and benchmarking tool.

Anticoagulants↗

PubMed2005

Conservative surgery and radiotherapy for stage I/II breast cancer using lung density correction: 10-year and 15-year results.

PURPOSE: Radiotherapy (RT) planning for breast cancer using lung density correction improves dose homogeneity. Its use obviates the need for a medial wedge, thus reducing scatter to the opposite breast. Although lung density correction is used at many centers in planning for early-stage breast cancer, long-term results of local control and survival have not been reported. Since 1984, we have used lung density correction for dose calculations at the University of Michigan. We now present our 10-year and 15-year results. METHODS AND MATERIALS: The records of 867 patients with Stage I/II breast cancer treated with breast-conserving surgery and RT with or without systemic therapy were reviewed. Tangential fields delivering 45-50 Gy to the whole breast calculated using lung density correction were used. A boost was added in 96.8% of patients for a total median dose of 61.8 Gy. RESULTS: With a median follow-up of 6.6 years (range, 0.2-18.9 years), 5-, 10-, and 15-year actuarial rates of in-breast tumor recurrence as only first failure were 2.2%, 3.6%, and 5.4%, respectively. With surgical salvage, the 15-year cumulative rate of local control was 99.7%. Factors that significantly predicted for increased rate of local recurrence in multivariate analysis were age </= 35 years, hazard ratio 4.8 (95% confidence interval [CI], 1.6-13.9) p = 0.004; negative progesterone receptor status, hazard ratio 6.8 (95% CI, 2.3-20.3) p = < 0.001; negative estrogen receptor status, hazard ratio 4.0 (95% CI, 1.5-11.1) p = 0.007; and lack of adjuvant tamoxifen therapy, hazard ratio 7.7 (95% CI, 1.7-33.3) p = 0.008. Relapse-free survival rates at 5, 10, and 15 years were 84.6%, 70.8%, and 55.9%, respectively; breast cancer-specific survival rates were 94.4%, 90.5%, and 86.9%, respectively; and corresponding estimates for overall survival were 89.7%, 75.7%, and 61.3%. CONCLUSIONS: Use of lung density correction was associated with high rates of local control, relapse-free survival, breast cancer-specific survival, and overall survival compared with other reported series of breast-conserving surgery and RT in early-stage disease. These results will serve as a benchmark against which newer radiation delivery strategies such as intensity-modulated RT and partial breast RT can be compared.

Adult↗

PubMed2005

Identifying genes from up-down properties of microarray expression series.

MOTIVATION: We consider any collection of microarrays that can be ordered to form a progression; for example, as a function of time, severity of disease or dose of a stimulant. By plotting the expression level of each gene as a function of time, or severity, or dose, we form an expression series, or curve, for each gene. While most of these curves will exhibit random fluctuations, some will contain a pattern, and these are the genes that are most likely associated with the quantity used to order them. RESULTS: We introduce a method of identifying the pattern and hence genes in microarray expression curves without knowing what kind of pattern to look for. Key to our approach is the sequence of ups and downs formed by pairs of consecutive data points in each curve. As a benchmark, we blindly identified genes from yeast cell cycles without selecting for periodic or any other anticipated behaviour. CONTACT: tmf20@cam.ac.uk SUPPLEMENTARY INFORMATION: The complete versions of Table 2 and Figure 4, as well as other material, can be found at http://www.lps.ens.fr/~willbran/up-down/ or http://www.tcm.phy.cam.ac.uk/~tmf20/up-down/

Algorithms↗

PubMed2004

Are tumor incidence rates from chronic bioassays telling us what we need to know about carcinogens?

Chronic bioassays for over 500 chemicals have been conducted under the auspices of the National Cancer Institute and/or the National Toxicology Program (NTP) to screen chemicals for carcinogenicity, providing a wealth of information about bioassays. Typically, chemicals are administered for two years to both sexes in each of one strain of rats and mice generally at the maximum tolerated dose (MTD), MTD/2, MTD/4 (in recent years), as well as unexposed control animals. In an attempt to ascertain the sensitivity of this bioassay to detect animal carcinogens tested at the MTD for the current experimental design, the false negative rate (failure to detect increased tumor rates) was investigated. This was accomplished by examining the tumor incidences from over 150 NTP bioassays and estimating the probability that a statistically significant (P0.01) dose-response trend would be obtained at one or more tissue sites in either sex of rats or mice if 200, rather than 50, animals were used per dose group. This provides an estimate of the proportion of chemicals that were not declared high-dose animal carcinogens due to the limited sample size of 50 animals per species-sex-dose group. In this series of chemicals tested, 97/156 (62%) were identified by the NTP to show some or clear evidence of carcinogenicity. With an increase of the number of animals per dose group from 50 to 200, it is estimated that 92% of these chemicals would show statistically significant (P0.01) dose-response trends at one or more tissue sites in either sex of rats or mice. Many of these chemicals are not genotoxic. Some chemicals had no structural alerts for carcinogenicity, but were tested because of potentially high human exposure. This analysis suggests that almost all of the chemicals selected would produce a statistically significant increase in tumor incidence at the MTD with larger sample sizes. Hence, this MTD bioassay screen is not distinguishing between true carcinogens and non-carcinogens. Rather, the screen is simply failing to detect the weaker carcinogens at the MTD. More than 30% of chemicals tested failed to detect statistically significant dose-response trends for tumors because of inadequate sample sizes of 50 animals per dose. Presumably, little or no action would have been taken to regulate exposures to these chemicals as potential carcinogens due to lack of a positive test result. This analysis does not suggest that most chemicals are carcinogenic at human exposure levels nor does it suggest that more than 50 animals should be tested per dose group. With an MTD that may produce a difference (up to 10%) in weight gain between treated and control animals, there quite possibly is cytotoxicity at the MTD. Increased carcinogenicity would be expected from increased opportunities for mutagenic activity during regenerative cell replication to compensate for cytotoxicity. Since it appears that almost all chemicals tested adequately at the MTD will demonstrate carcinogenicity, it is tempting to surmise that this is due in large part to one or more nearly universal modes of action, such as, regenerative cell replication at the MTD rather than due to some unique carcinogenic property of a chemical. That is, the current bioassay possibly is just primarily a screen for the more potent cytotoxins at the MTD, rather than a screen specifically for carcinogenicity. This issue should be examined and suggests that cytotoxicity and cell proliferation should be considered in setting the MTD, particularly for non-genotoxic (non-DNA reactive) chemicals. From a public health view, it is prudent to assume that most chemicals could demonstrate increased tumor incidence rates at the MTD in rodents. The current standard NTP bioassay provides sufficient data to estimate a benchmark dose associated with a specified low tumor incidence to be used as a point-of-departure for cancer risk assessments. The question that should be investigated by a bioassay is not whether a chemical is a carcinogen at the MTD, but what is the relationship between dose and cytotoxicity and/or other modes of action that could produce an excess of tumors?

Animals↗

PubMed1993

The developmental toxicity of inhaled methanol in the CD-1 mouse, with quantitative dose-response modeling for estimation of benchmark doses.

The developmental toxicity of the alternative motor vehicle fuel methanol was assessed in mice by the inhalation route. Pregnant CD-1 mice were exposed to 1,000, 2,000, 5,000, 7,500, 10,000, or 15,000 ppm methanol for 7 hr/day on days 6-15 of gestation. Sham-exposed controls were exposed to filtered air under similar conditions. Additional control groups were left in their home cages either unhandled or food-deprived for 7 hr/day to match the food deprivation experienced by the exposed mice. Dams were observed twice daily and weighed on alternate days during the exposure period. Blood methanol concentrations were determined in some mice on gestation days 6, 10, and 15. On day 17, the remaining mice were weighed and killed and the gravid uteri removed. Implantation sites, live and dead fetuses and resorptions were counted, fetuses were examined externally and weighed as a litter. Half of each litter was examined for skeletal morphology and the other half of each litter was examined for internal soft tissue anomalies. One dam died in each of the 7,500, 10,000, and 15,000 ppm methanol exposure groups, but no dose-response relationship was evident for maternal death. The sham-exposed and food-deprived controls as well as all methanol exposed dams gained less weight than did unexposed dams fed ad libitum, but methanol did not exacerbate this effect. Significant increases in the incidence of exencephaly and cleft palate were observed at 5,000 ppm and above, increased embryo/fetal death at 7,500 ppm and above (including an increasing incidence of full-litter resorptions), and reduced fetal weight at 10,000 ppm and above. A dose-related increase in cervical ribs or ossification sites lateral to the seventh cervical vertebra was significant at 2,000 ppm and above. Thus, the NOAEL for the developmental toxicity in this study was 1,000 ppm. A log-logistic dose response model was applied to the incidence data for exencephaly, cleft palate, resorption and cervical rib, and maximum likelihood estimates (MLEs) and benchmark dosages (BDs, the lower 95% confidence interval of the MLEs) corresponding to 1% and 5% added risk above background were calculated. The MLE for 5% added combined risk of having either exencephaly or cleft palate or being resorbed was 3667 ppm, and the corresponding BD was 3,078 ppm. For cervical rib, the 5% added risk values for the MLE and BD were 824 and 305 ppm, respectively. The BDs for 1% added risk were 1915 ppm for exencephaly, cleft palate or resorption, and 58 ppm for cervical rib.(ABSTRACT TRUNCATED AT 400 WORDS)

Abnormalities, Drug-Induced↗

PubMed2005

Evaluation of N50 neutron slab monitor detection efficiency with TRIPOLI-4.3 Monte Carlo code.

Monte Carlo code TRIPOLI-4.3 has been used to evaluate the N50 neutron slab monitor detection efficiency benchmark organised by the non-destructive assay (NDA) working group of European Safeguards Research and Development Association (ESARDA). The lattice geometry of TRIPOLI-4.3 was applied to simplify the modelling of the N50 monitor, which consists of four 3He tubes embedded in a high-density polyethylene (HDPE) moderator. Using additional HDPE slabs and/or Cd sheets, 10 geometry configurations with different states of moderation were considered in this study. Two cross section libraries from ENDF/B-VI.4 and JEF2.2 and three representations of the 252Cf fission spectrum were investigated and the calculation experiment (C/E) ratios were discussed. The perturbation option was used in order to study the sensitivity to the HDPE density. The S(alpha,beta) thermal scattering in HDPE was also tested to quantify its impact on the N50 detection efficiency calculations.

Algorithms↗