SEARCH · PubMed Health

Results for “benchmark dose analysis”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 55 records · Page 3Linked to original sources

PubMed2002

Evaluation of the benchmark dose method for dichotomous data: model dependence and model selection.

The benchmark dose (BMD) method was evaluated using the USEPA BMD software. Dose-response data on cleft palate and hydronephrosis for a number of related polyhalogenated aromatic compounds were obtained from the literature. According to chi(2) test statistics, each dichotomous USEPA model failed to adequately describe only 1 of 12 cleft palate data sets. For hydronephrosis, the models were discriminated to a higher extent according to global goodness-of-fit. NOAELs for cleft palate corresponded to BMDLs (the approximate lower confidence limit on the BMD) for extra risks in the range of 5% or below. Model dependence of the BMDL estimate was more pronounced at lower levels of benchmark response (BMR). A BMR of 5% (extra risk) is recommended for cleft palate since model differences at this level were limited for all data. In addition, at BMRs of 5-10% the BMDL for all models was little affected by the specified confidence limit size (in the 90-99% range). For BMDL determination a conservative model selection approach was applied. At the suggested level of BMR (5%) this procedure resulted in use of the same model (multistage model) for the cleft palate endpoint in general. Akaike's information criterion (AIC) was considered for comparison between models. Determination of appropriateness of use of such methods in dose-response applications requires further analysis.

Abnormalities, Drug-Induced↗

PubMed2004

Bone marrow dosimetry using blood-based models for radiolabeled antibody therapy: a multiinstitutional comparison.

UNLABELLED: Standardization of marrow dosimetry is of considerable importance when estimating dose-response for a multicentered clinical trial involving radionuclide therapy. However, it is only within the past five years that the intercomparison of marrow dosimetry results among separate clinical trials that use the same agent has become scientifically feasible. In this work, we have analyzed reported marrow dosimetry results from radioimmunotherapy trials and recalculated marrow absorbed doses at a central facility using a standard blood model with patient-specific source data. The basic approach used in the American Association of Physicists in Medicine (AAPM)/Sgouros marrow dosimetry methodology was common to calculation performed at all participating institutions, including the central facility. Differences in dose estimates associated with starting assumptions and the exact implementation of the AAPM/Sgouros calculation methodology used by the source institutions and the central facility were quantified and compared. METHODS: Data from 22 patients enrolled in radiolabeled antibody clinical trials were randomly selected from 7 participating institutions for the assessment of marrow dose. The analysis was restricted to those patients who were treated with 131I- or 186Re-labeled antibody and had no marrow involvement. Calculation of bone marrow dose at each participating institution was unique to the trial or institution, but all used some form of the AAPM/Sgouros blood model approach. The central facility adopted a marrow dosimetry model based on the AAPM/Sgouros model for radiolabeled antibodies using the standard MIRD approach to the remainder-of-body contribution. A standardized approach to account for variations in patient mass was used for the remainder-of-body component. To simplify clinical implementation, regional marrow uptake and time-dependent changes in the marrow-to-blood concentration ratio were not included. Methods of formatting the collection of standard datasets useful in defining dose-response parameters are also presented. RESULTS: Bone marrow doses were calculated according to the method described for each of the 22 patients based on the patient-specific data supplied by the participating institutions. These values were then individually compared with the marrow doses originally reported by each institution. Comparison of the two calculation methods was expressed as a ratio of the marrow doses for each patient. The mean ratio for the dose estimates at the participating institution calculation compared with the central laboratory value was 0.920 +/- 0.259 (mean +/- SD), with a range from 0.708 to 1.202. CONCLUSION: The independent use of the AAPM/Sgouros method blood model approach to marrow dosimetry has brought these dose estimates to within 30% of the results obtained centrally compared with substantially higher uncertainties reported previously. Variations in calculation methodology or initial assumptions adopted by individual institutions may still contribute significant uncertainty to dose estimates, even when the same data are used as a starting point for the calculation comparison shown here. A clinically relevant, standard method for marrow dosimetry for radiolabeled antibodies is proposed as a benchmark for intercomparison purposes. A parameter sensitivity analysis and a summary discussion of the use of this model for potentially improving dose-response data correlation are also presented.

Adult↗

PubMed1996

Application of a biologically-based RFD estimation method to tetrachlorodibenzo-p-dioxin (TCDD) mediated immune suppression and enzyme induction.

The current methods for a reference dose (RfD) determination can be enhanced through the use of biologically-based dose response analysis. Methods developed here utilizes information from tetrachlorodibenzo-p-dioxin (TCDD) to focus on noncancer endpoints, specifically TCDD mediated immune system alterations and enzyme induction. Dose-response analysis, using the Sigmoid-Emax (EMAX) function, is applied to multiple studies to determine consistency of response. Through the use of multiple studies and statistical comparison of parameter estimates, it was demonstrated that the slope estimates across studies were very consistent. This adds confidence to the subsequent effect dose estimates. This study also compares traditional methods of risk assessment such as the NOAEL/safety factor to a modified benchmark dose approach which is introduced here. Confidence in the estimation of an effect dose (ED10) was improved through the use of multiple datasets. This is key to adding confidence to the benchmark dose estimates. In addition, the Sigmoid-Emax function when applied to dose-response data using nonlinear regression analysis provides a significantly improved fit to data increasing confidence in parameter estimates which subsequently improve effect dose estimates.

Animals↗

PubMed1998

Calculation of benchmark doses for reproductive and developmental toxicity observed after exposure to isopropanol.

Reproductive, including developmental, toxicity risk assessment has typically relied on estimation of toxicity criteria values derived from no-observed-adverse-effect levels (NOAELs). The benchmark dose (BMD) approach has been proposed as an alternative that avoids problems with NOAELs. In this analysis of the reproductive and developmental toxicity observed in a multigeneration study of rats exposed to isopropanol, the BMD approach has been applied to all effects exhibiting significant dose-response relationships. The BMD estimates were very consistent across models and across end points; they were within the range of doses (100 to 500 mg/kg/day) that has been suggested as being the NOAEL. The use of the BMD approach for analysis of isopropanol reproductive toxicity is shown to avoid the experiment-specific argument of whether a particular treatment has induced statistically significant differences, compared to controls, in favor of the estimation of experiment-independent doses corresponding to risk levels of interest. The consistency of the BMD estimates, with values of about 420 mg/kg/day, suggests that, for isopropanol, the available multigeneration study data may provide a suitable basis for considering safe exposure.

2-Propanol↗

PubMed2005

Simultaneous confidence bounds for low-dose risk assessment with nonquantal data.

We study the use of simultaneous confidence bounds for making low-dose inferences in quantitative risk analysis. Confidence limits are constructed for outcomes measured on a continuous scale, assuming a simple linear model for the observed response. From the simultaneous confidence bounds, simultaneous lower limits on the benchmark dose associated with a particular risk are also constructed.

Animals↗

PubMed2002

An analysis of MCNP cross-sections and tally methods for low-energy photon emitters.

Monte Carlo calculations are frequently used to analyse a variety of radiological science applications using low-energy (10-1000 keV) photon sources. This study seeks to create a low-energy benchmark for the MCNP Monte Carlo code by simulating the absolute dose rate in water and the air-kerma rate for monoenergetic point sources with energies between 10 keV and 1 MeV. The analysis compares four cross-section datasets as well as the tally method for collision kerma versus absorbed dose. The total photon attenuation coefficient cross-section for low atomic number elements has changed significantly as cross-section data have changed between 1967 and 1989. Differences of up to 10% are observed in the photoelectric cross-section for water at 30 keV between the standard MCNP cross-section dataset (DLC-200) and the most recent XCOM/NIST tabulation. At 30 keV, the absolute dose rate in water at 1.0 cm from the source increases by 7.8% after replacing the DLC-200 photoelectric cross-sections for water with those from the XCOM/NIST tabulation. The differences in the absolute dose rate are analysed when calculated with either the MCNP absorbed dose tally or the collision kerma tally. Significant differences between the collision kerma tally and the absorbed dose tally can occur when using the DLC-200 attenuation coefficients in conjunction with a modern tabulation of mass energy-absorption coefficients.

Air↗

PubMed1997

An approach for modeling noncancer dose responses with an emphasis on uncertainty.

This paper presents an approach for characterizing the probability of adverse effects occurring in a population exposed to dose rates in excess of the Reference Dose (RfD). The approach uses a linear threshold (hockey stick) model of response and is based on the current system of uncertainty factors used in setting RfDs. The approach requires generally available toxicological estimates such as No-Observed-Adverse-Effect Levels (NOAELs) or Benchmark Doses and doses at which adverse effects are observed in 50% of the test animals (ED50s). In this approach, Monte Carlo analysis is used to characterize the uncertainty in the dose response slope based on the range and magnitude of the key sources of uncertainty in setting protective doses. The method does not require information on the shape of the dose response curve for specific chemicals, but is amenable to the inclusion of such data. The approach is applied to four compounds to produce estimates of response rates for dose rates greater than the RfD.

Acetamides↗

PubMed2005

Critical dose of lead affecting postural balance in workers.

BACKGROUND: The threshold blood lead (BPb) level for nervous system dysfunction in adults has been estimated to be 30-40 microg/dl. This study was carried out to estimate the critical dose of lead affecting the neuromotor function in workers by introducing the benchmark dose (BMD) approach, as well as to identify the specific postural sway to lead exposure. METHODS: Postural sway parameters with spectral analysis were compared between 121 lead workers with BPb levels of 6-89 (mean 40) microg/dl and 60 unexposed controls. RESULTS: All sway parameters, except for sagittal sways with eyes open, were significantly larger in the lead workers than in the controls; also, the Romberg quotient for sagittal sway was significantly higher in the lead workers. The BPb level in the lead workers was significantly related to sagittal sways at 1-2 Hz and 2-4 Hz with eyes open, and sagittal and transversal sways at 1-2 Hz and 2-4 Hz with eyes closed. The BMD levels of BPb (i.e., lower 95% confidence limits of BMD) were estimated to be 12.1-17.3 (mean 14.4) microg/dl for postural sway. CONCLUSIONS: Neuromotor dysfunction in lead workers may be initiated at BPbs below the level previously accepted as effectless, and be characterized mainly by an increased sway of high frequency (1-4 Hz) in the sagittal direction with eyes closed (high Romberg quotient).

Case-Control Studies↗

PubMed2002

Critical issues in benchmark calculations from continuous data.

The benchmark dose (BMD) is a dose that causes a specified low level of additional risk and is estimated using a statistical dose-response analysis. Regulatory agencies are using a statistical lower bound on the BMD in the place of the NOAEL for establishing exposure limits. However, there are still several issues regarding the BMD for which no clear consensus has emerged, particularly with respect to calculation of BMD from continuous response data. These include: (1) how to define the BMD from continuous data so that they are comparable to BMD derived from binary data, (2) what dose-response models and levels of additional risk should be used to calculate the BMD. The "hybrid" approach (Gaylor and Slikker, 1990; Crump, 1995) expresses the BMD from continuous data in terms that are directly comparable to those obtained using binary data. Several features of the hybrid approach are examined, with the emphasis on application to epidemiological data. The effect on the BMD of converting continuous data to binary form is quantified. Model uncertainty is explored, and the need for controlling this uncertainty by restricting the class of allowable models is demonstrated. Control data, which are often not available in epidemiological studies, are shown to have a limited effect upon the BMD so long as the model for the mean response is linear or convex. Such models are also biologically plausible, at least at low doses. Based on these and other considerations, suggestions are made for selecting a model for applying the hybrid approach and for selecting the level of additional risk on which to base the BMD.

Algorithms↗

PubMed1994

Modeling fetal death and malformation in developmental toxicity studies.

We review approaches to dose-response modeling and risk assessment for binary data from developmental toxicity studies. In particular, we focus on jointly modeling fetal death and malformation and use a continuation ratio formulation of the multinomial distribution to provide a model for risk. Generalized estimating equations are used to account for clustering of animals within litters. The fitted model is then used to calculate doses corresponding to a specified level of excess risk. Two methods of arriving at a lower confidence limit or Benchmark dose are illustrated and compared. We also discuss models based on single binary end points and compare our approach to a binary analysis of whether or not the animal was 'affected' (either dead or malformed). The models are illustrated using data from four developmental toxicity studies in EG, DEHP, TGDM, and DYME conducted through the National Toxicology Program.

Abnormalities, Drug-Induced↗

PubMed2003

Utilizing data from multiple studies (meta-analysis) to determine effective dose-duration levels. Example: rats and mice exposed to hydrogen sulfide.

The objective of this exercise was to incorporate as much data as possible from multiple studies, that may differ in exposure durations, to derive a chemical-specific dose-duration response curve from which to identify toxicity markers (e.g., ED01, benchmark dose, and LD50). This has the advantage of incorporating more information than single-study assessments to improve estimates and reduce confidence intervals, and determining toxicity markers as functions of exposure duration as well as dose. The example used mortality for rats and mice, analyzed separately, from acute exposure to hydrogen sulfide (dose refers to airborne concentration of H(2)S). Statistical methods were applied to determine when data from different studies could be pooled. EC01, EC10, and EC50 (doses with response rates of 1, 10, and 50%) were estimated, with 95% confidence intervals, at durations of 5, 10, and 30 min, and 1, 2, 4, and 6 h. A single dose-duration response curve for mortality was fit to the rat data for exposures of 5 min, 10 min, 30 min, and 1h, using a logistic curve additive in log(dose) and log(duration). Separate fits of that model were required, however, at 2, 4, and 6h, due to an increasing impact of duration relative to concentration as duration increased. The curves for rats fit the data exceedingly well and exhibited a threshold-like response followed by a steep incline as concentration increased. There were fewer data for mice but the response pattern for mortality clearly differed from rats. This example demonstrates the feasibility of extending the concept of single-study benchmark doses to multiple-study dose-duration benchmarks, using U.S. EPA's program CatReg. Similar applications to long-term animal studies could be considered.

Air Pollutants↗

PubMed1996

Dose-response analysis in risk assessment: evaluation of behavioral specificity.

Several methods of quantitative risk assessment that have been described recently are particularly applicable to neurotoxic end points. These methods can be broadly divided into two types of approaches based on their treatment of dose-response data to estimate risks. Benchmark approaches estimate risks using variability in response to a fixed dose level in comparison with background control variability. Probabilistic approaches estimate risks using the variability in the dose to produce a small effect in the sample population. The current report seeks to extend the development of probabilistic approaches for neurotoxic end points. Because behavioral data are often used to assess therapeutic efficacy as well as toxicity (unwanted effects), this analysis focused on the relative risks of producing these effects with the same agent. The therapeutic potential of GBR 12909 was determined by its ability to decrease cocaine-maintained responding in monkeys. The effects of this agent were also assessed in the same monkeys using food-maintained responding to provide an indication of behavioral toxicity. GBR 12909 decreased both behaviors, with complete decreases on drug-seeking behavior occurring at doses that had minimal effects on food-maintained responding. The difference in the estimates of doses to decrease drug-seeking and food-maintained behavior suggested that specific therapeutic effects could be obtained in the absence of unwanted side effects for a definable proportion of the population. These results also suggest that multiple behavioral end points can be useful for identifying specific effects of chemicals for the purposes' of risk assessment.

Animals↗

PubMed2004

Dose-response for retinoic acid-induced forelimb malformations and cleft palate: a comparison of computerized image analysis and visual inspection.

BACKGROUND: The objectives of this study were to (1) compare two techniques (computerized image analysis and visual morphological evaluation) for the assessment of fetal forelimb malformations and (2) increase the robustness of the dose-response curve for forelimb and cleft palate malformations resulting from all-trans retinoic acid (RA) exposure in GD 11 mice. METHODS: Pregnant CD-1 mice were administered a single oral dose of all-trans RA (0, 2.5, 10, 30, 60, or 100 mg/kg) on GD 11. GD 18 fetuses were examined for malformations using visual morphological scoring and computerized image analysis. RESULTS: Dose-dependent changes occurred in the size and shape of the humerus, radius, and ulna based on both assessment methodologies. The most sensitive indicators for the lowest effect level (10 mg/kg) on forelimbs were roundness, a shape measurement determined by image analysis, and visual morphological scoring. For all other bone measurements (proximal and distal width, area, length, and perimeter), the lowest effect level was 30 mg/kg. The maximum effect for limb defects and total malformed fetuses was seen at 60 mg/kg and higher. Incidence of cleft palate increased over the entire range of administered doses reaching a maximum of 74% (100 mg/kg). CONCLUSIONS: Overall, results indicate that computerized image analysis was no more sensitive in detecting changes in the humerus, radius, and ulna than gross visual examination. Dose-response modeling of developmental endpoints yielded comparable benchmark dose levels for long bones and cleft palate that ranged from 0.24 to 7.6 mg/kg all-trans RA. Birth Defects Res B 71:289-295, 2004.

Abnormalities, Drug-Induced↗

PubMed2006

Relation between benchmark dose and no-observed-adverse-effect level in clinical research: effects of daily alcohol intake on blood pressure in Japanese salesmen.

The benchmark dose (BMD) is defined as the dose that corresponds to a specific change in an adverse response compared to the response in unexposed subjects, and the lower 95% confidence limit is termed the benchmark dose level (BMDL). In this study, the threshold of daily ethanol intake affecting blood pressure was calculated by both the BMD approach and multiple logistic regression analysis to clarify the relation between the BMDL and no-observed-adverse-effect level (NOAEL). Systolic and diastolic blood pressures (SBP and DBP) and daily ethanol intake were explored in 1,100 Japanese salesmen. The SBP and DBP were positively related to daily ethanol intake (p < 0.001) when adjusting for possible confounders such as age, body mass index, and smoking status. The adjusted risk for hypertension (SBP >or= 140 mmHg or DBP >or= 90 mmHg) increased significantly when daily ethanol intake exceeded 60 g/day, and the categorical dose of interest was 60.1-90 g/day. The BMDL and BMD of ethanol intake for increased SBP and DBP were estimated to be approximately 60 and 75 g/day, respectively. These findings suggest that the BMDL and BMD correspond to the NOAEL and lowest-observed-adverse-effect level, respectively, if the sample number of clinical data is large enough to confirm the dose-response association.

Adolescent↗

PubMed2004

Kinetic modeling of beta-chloroprene metabolism: II. The application of physiologically based modeling for cancer dose response analysis.

beta-Chloroprene (2-chloro-1,3-butadiene; CD), which is used in the synthesis of polychloroprene, caused significant incidences of several tumor types in B6C3F1 mice and Fischer rats, but not in Wistar rats or Syrian hamsters. This project investigates the relevance of the bioassay lung tumor findings to human health risk by developing a physiologically based toxicokinetic (PBTK) model and exploring a tissue specific exposure-dose-response relationship. Key steps included identification of the plausible genotoxic mode of action, experimental quantification of tissue-to-air partition coefficients, scaling of in vitro parameters of CD metabolism for input into the PBTK model, comparing the model with in vivo experimental gas uptake data, selecting an appropriate tissue dosimetric, and predicting a corresponding human exposure concentration. The total daily milligram amount of CD metabolized per gram of lung was compared with the animal bioassay response data, specifically combined bronchiolar adenoma/carcinoma. The faster rate of metabolism in mouse lung agreed with the markedly greater incidence of lung tumors compared with the other rodent species. A lung tissue dose was predicted for the combined rodent lung tumor bioassay data at a 10% benchmark response. A human version of the PBTK model predicted that the lung tissue dose in humans would be equivalent to continuous lifetime daily exposure of 23 ppm CD. PBTK model sensitivity analysis indicated greater dependence of model predictions of dosimetry on physiological than biochemical parameters. The combined analysis of lung tumor response across species using the PBTK-derived internal dose provides an improved alternative to default pharmacokinetic interspecies adjustments for application to human health risk assessment.

Adipose Tissue↗

PubMed1995

Reanalysis of dose-response data from the Iraqi methylmercury poisoning episode.

Applying a hockey stick parametric dose-response model to data on late or retarded development in Iraqi children exposed in utero to methylmercury, with mercury (Hg) exposure characterized by the peak Hg concentration in mothers' hair during pregnancy, Cox et al. calculated the "best statistical estimate" of the threshold for health effects as 10 ppm Hg in hair with a 95% range of uncertainty of between 0 and 13.6 ppm. A new application of the hockey stick model to the Iraqi data shows, however, that the statistical upper limit of the threshold based on the hockey stick model could be as high as 255 ppm. Furthermore, the maximum likelihood estimate of the threshold using a different parametric model is virtually zero. These and other analyses demonstrate that threshold estimates based on parametric models exhibit high statistical variability and model dependency, and are highly sensitive to the precise definition of an abnormal response. Consequently, they are not a reliable basis for setting a reference dose (RfD) for methylmercury. Benchmark analyses and statistical analyses useful for deriving NOAELs are also presented. We believe these latter analyses--particularly the benchmark analyses--generally form a sounder basis for determining RfDs than the type of hockey stick analysis presented by Cox et al. However, the acute nature of the exposures, as well as other limitations in the Iraqi data suggest that other data may be more appropriate for determining acceptable human exposures to methylmercury.

Child↗

PubMed2005

Comparative analyses of linac and Gamma Knife radiosurgery for trigeminal neuralgia treatments.

Dedicated linac-based radiosurgery has been reported for trigeminal neuralgia treatments. In this study, we investigated the dose fall-off characteristics and setup error tolerance of linac-based radiosurgery as compared with standard Gamma Knife radiosurgery. In order to minimize the errors from different treatment planning calculations, consistent imaging registration, dose calculation and dose volume analysis methods were developed and implemented for both Gamma Knife and linac-based treatments. Intra-arc setup errors were incorporated into the treatment planning process of linac-based deliveries. The effects of intra-arc setup errors with increasing number of arcs were studied and benchmarked against Gamma Knife deliveries with and without plugging patterns. Our studies found equivalent dose fall-off properties between Gamma Knife and linac-based radiosurgery given a sufficient number of arcs (>7) and small intra-arc errors (<0.5 mm) were satisfied for linac-based deliveries. Increasing the number of arcs significantly decreased the variations in the dose fall-off curve at the low isodose region (e.g. from 40% to 10%) and also improved dose uniformity at the high isodose region (e.g. from 70% to 90%). As the number of arcs increased, the effects of intra-arc setup errors on the dose fall-off curves decreased. Increasing the number of arcs also reduced the integral dose to the distal normal brain tissues. In conclusion, linac-based radiosurgery produces equivalent dose fall-off characteristics to Gamma Knife radiosurgery with a high number of arcs. However, one must note the increased treatment time for a large number of arcs and isocentre accuracies.

Dose-Response Relationship, Radiation↗

PubMed2004

A comparison of microbial dose-response models fitted to human data.

A study of eight mathematical dose-response models for microbial risk assessment was conducted using infectivity and illness data on a variety of microbial pathogens from published studies with human volunteers. The purpose was to evaluate variability among the models for human microbial dose-response data in order to determine whether two-parameter models might suffice for most microbial dose-response data or whether three-parameter models should generally be fitted. Model variability was measured in terms of estimated ED01s and ED10s, with the view that these effective dose levels correspond to the lower and upper limits of the 1-10% risk range generally recommended for establishing benchmark doses in risk assessment. An investigation of the ranks of the ED01 and ED10 values among the models led to the conclusion that the two-parameter models captured at least as much uncertainty as the three-parameter models for the data examined. A further evaluation of the two-parameter models did not result in the selection of one "best" model, but it did provide some insights into the models' relative behavior. The model uncertainty analysis proposed by Kang et al. [Regulat. Toxicol. Pharmacol. 32 (2000) 68] using four two-parameter models was reinforced.

Algorithms↗