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Biomedical subjects

A J Bailer

Publications and source records attributed to A J Bailer.

At least 19 recordsLinked to original sources
PubMed1995

Modeling epidemiologic studies of occupational cohorts for the quantitative assessment of carcinogenic hazards.

Epidemiologic studies of occupational cohorts have played a major role in the quantitative assessment of risks associated with several carcinogenic hazards and are likely to play an increasingly important role in this area. Relatively little attention has been given in either the epidemiologic or the risk assessment literature to the development of appropriate methods for modeling epidemiologic data for quantitative risk assessment (QRA). The purpose of this paper is to review currently available methods for modeling epidemiologic data for risk assessment. The focus of this paper is on methods for use with retrospective cohort mortality studies of occupational groups for estimating cancer risk, since these are the data most commonly used when epidemiologic information is used for QRA. Both empirical (e.g., Poisson regression and Cox proportionate hazards model) and biologic (e.g., two-stage models) models are considered. Analyses of a study of lung cancer among workers exposed to cadmium are used to illustrate these modeling methods. Based on this example it is demonstrated that the selection of a particular model may have a large influence on the resulting estimates of risk.

Cadmium↗
PubMed1995

Exploratory analysis of population genetic assessment as a water quality indicator. I. Pimephales notatus.

Biological sampling has been implemented to assess water quality in many states. The purpose of this study was to examine whether genetic diversity and structure of Pimephales notatus could serve as effective biomarkers of exposure to anthropogenic stressors by comparing genetic measures with other biological indicators of water quality. Fish were collected from 15 sites on eight streams by the Ohio Environmental Protection Agency as part of their stream water quality evaluation program. Values for the Index of Biotic Integrity (IBI) and the Invertebrate Community Index (ICI) were determined for these 15 sites. Starch gel electrophoresis was used to collect genetic data for seven variable enzyme loci. Genetic diversity measures were not associated with site IBI or ICI values. However, the range of site IBI and ICI values was limited. The proportion of individuals not expressing esterase locus 3 could be used to predict IBI; IBI decreased as the proportion of nonexpression increased. Allele and genotype frequency differences were observed between sites on the Little Scioto River, the one stream with a large difference in IBI and ICI values between sites. This study suggested that allele and genotype frequencies may have been impacted without affecting overall species diversity.

Alleles↗
PubMed1995

Exploratory analysis of population genetic assessment as a water quality indicator. II. Campostoma anomalum.

Biological monitoring programs to assess contaminant-induced impacts in aquatic systems are being developed and implemented by several federal agencies and many states. Genetic diversity and allozyme frequency may be valuable indicators of such impact because they are both sensitive to exposure and ecologically relevant in populations. The purpose of this study was to examine whether genetic diversity and structure of Campostoma anomalum populations could serve as effective biomarkers of exposure to anthropogenic stress by comparing genetic measures with other biological indicators of water quality. Fish were collected from 14 sites on seven streams by the Ohio Environmental Protection Agency as part of their stream water quality evaluation program. Values for the Index of Biological Integrity (IBI) and the Invertebrate Community Index (ICI) were determined for these 14 sites. Starch gel electrophoresis was used to collect genetic data for eight variable enzyme loci. Genetic diversity measures were not associated with site IBI or ICI values. However, the range of site IBI and ICI values was limited. Allele and genotype frequencies were significantly different at the point source compared to sites upstream and downstream indicating that genetic structure may be an indicator of water quality that is sensitive enough to detect change prior to species loss.

Acid Phosphatase↗
PubMed1994

The impact of exercise and intersubject variability on dose estimates for dichloromethane derived from a physiologically based pharmacokinetic model.

Andersen et al. and Reitz et al. have developed physiologically based pharmacokinetic models for the human metabolism of methylene chloride (dichloromethane; DCM) and have advanced the hypothesis that the carcinogenicity of DCM is related to target organ metabolism of DCM by glutathione S-transferase (GST). The models included physiological parameters appropriate for humans at rest and metabolic parameters based on average rates of DCM metabolism. Increasing the model parameters describing cardiac output, alveolar ventilation, and blood flows to tissues from resting values to values consistent with light work conditions, and assuming a 25 ppm exposure for an 8-hr work day, increases the estimated GST-metabolized dose for human liver by a factor of 2.9 compared to the GST-metabolized does estimated of Reitz et al. These modifications also increase the GST-metabolized dose to the lung by 2.4-fold. If the model is also modified to reflect individual variation in DCM metabolism (in addition to the modifications for light work conditions), the estimated GST-metabolized dose for human liver ranges from 0 to as much as 5.4-fold greater than the dose estimated by Reitz et al. The GST-metabolized dose to the lung ranges from 0 to as much as 3.6-fold greater than the dose estimated by Reitz et al. These results indicate that some occupationally-exposed individuals may receive GST-metabolized doses several-fold greater than the Reitz et al. human dose estimates.

Adipose Tissue↗
PubMed1994

Statistical approaches for analyzing mutational spectra: some recommendations for categorical data.

In studies examining the patterns or spectra of mutational damage, the primary variables of interest are expressed typically as discrete counts within defined categories of damage. Various statistical methods can be applied to test for heterogeneity among the observed spectra of different classes, treatment groups and/or doses of a mutagen. These are described and compared via computer simulations to determine which are most appropriate for practical use in the evaluation of spectral data. Our results suggest that selected, simple modifications of the usual Pearson X2 statistic for contingency tables provide stable false positive error rates near the usual alpha = 0.05 level and also acceptable sensitivity to detect differences among spectra. Extensions to the problem of identifying individual differences within and among mutant spectra are noted.

Base Sequence↗
PubMed1994

Estimating upper confidence limits for extra risk in quantal multistage models.

Multistage models are frequently applied in carcinogenic risk assessment. In their simplest form, these models relate the probability of tumor presence to some measure of dose. These models are then used to project the excess risk of tumor occurrence at doses frequently well below the lowest experimental dose. Upper confidence limits on the excess risk associated with exposures at these doses are then determined. A likelihood-based method is commonly used to determine these limits. We compare this method to two computationally intensive "bootstrap" methods for determining the 95% upper confidence limit on extra risk. The coverage probabilities and bias of likelihood-based and bootstrap estimates are examined in a simulation study of carcinogenicity experiments. The coverage probabilities of the nonparametric bootstrap method fell below 95% more frequently and by wider margins than the better-performing parametric bootstrap and likelihood-based methods. The relative bias of all estimators are seen to be affected by the amount of curvature in the true underlying dose-response function. In general, the likelihood-based method has the best coverage probability properties while the parametric bootstrap is less biased and less variable than the likelihood-based method. Ultimately, neither method is entirely satisfactory for highly curved dose-response patterns.

Animals↗
PubMed1994

Model-based time extrapolation for quantal response studies.

It is often desired to compare chemicals with respect to toxicity for purposes of priority setting in regulation. Long-term carcinogenicity studies are frequently used as the basic data for such exercises. When the results of these studies for different chemicals are compared, many confounders potentially arise. One confounder is that these studies may have been conducted for different study lengths. In this case, converting the results of these studies to a common "standard" time length would be of interest. We propose an adjustment to modify the results of a study with a particular study length to a standard time length. This adjustment is based on a simple stochastic model for carcinogenicity studies. We illustrate the application of this adjustment with an example of a chemical that has been studied by the National Toxicology Program.

Animals↗
PubMed1993

Comparing toxicologic and epidemiologic studies: methylene chloride--a case study.

Exposure to methylene chloride induces lung and liver cancers in mice. The mouse bioassay data have been used as the basis for several cancer risk assessments. The results from epidemiologic studies of workers exposed to methylene chloride have been mixed with respect to demonstrating an increased cancer risk. The results from a negative epidemiologic study of Kodak workers have been used by two groups of investigators to test the predictions from the EPA risk assessment models. These two groups used very different approaches to this problem, which resulted in opposite conclusions regarding the consistency between the animal model predictions and the Kodak study results. The results from the Kodak study are used to test the predictions from OSHA's multistage models of liver and lung cancer risk. Confidence intervals for the standardized mortality ratios (SMRs) from the Kodak study are compared with the predicted confidence intervals derived from OSHA's risk assessment models. Adjustments for the "healthy worker effect," differences in length of follow-up, and dosimetry between animals and humans were incorporated into these comparisons. Based on these comparisons, we conclude that the negative results from the Kodak study are not inconsistent with the predictions from OSHA's risk assessment model.

Animals↗
PubMed1993

Time-to-tumour risk assessment for 1,3-butadiene based on exposure of mice to low doses by inhalation.

The excess risk for cancer due to lifetime occupational exposure to 1,3-butadiene at the proposed US Occupational Safety and Health Administration standard of 2 ppm was estimated on the basis of a quantitative risk assessment. The risk assessment was based on a recent study by the US National Toxicology Program of the carcinogenicity of butadiene in B6C3F1 mice, using exposure concentrations ranging from 6.25 to 625 ppm butadiene and controls. Cancer risks were estimated using a multistage Weibull time-to-tumour model; the dose was based on the external butadiene concentration, owing to the low-dose linearity of butadiene metabolism. The parameters of the time-to-tumour model were estimated for seven tumour sites in male mice and nine in female mice. The risk estimates were extrapolated from mice to humans on the basis of body weight raised to the three-fourths power, and the median lifespan of mice was equated to a human lifespan of 74 years. Estimates of excess risk for lifetime occupational exposure (8 h/day, 5 days/week, 50 weeks/year, for 45 years) to 2 ppm butadiene ranged from 0.2 per 10,000 workers, based on female mouse heart haemangiosarcomas, to 600 per 10,000 workers, based on female mouse lung tumours. An analysis was performed to assess the effects of varying the modelling assumptions (incidental versus fatal tumours, inclusion or exclusion of the 625-ppm dose group, and basis for interspecies scaling) on the risk estimates from the female mouse lung tumour model. Depending on the assumptions, estimates of lifetime excess risk derived from the female mouse lung model ranged from 60 per 10,000 to 1600 per 10,000. These results suggest that exposures to butadiene in the work place should be reduced to the lowest feasible level.

Administration, Inhalation↗
PubMed1993

A measure of tumorigenic potency incorporating dose-response shape.

Many researchers have considered the problem of ranking chemical agents based on their carcinogenic potency. Sawyer et al. (1984, Biometrics 40, 27-40) proposed a carcinogenic potency estimate that incorporates both intercurrent mortality and background tumor rates. Since then, many authors have either generalized the method outlined by Sawyer et al. or developed their own method based on a slightly different adjustment for treatment-related changes in survival. None of these methods, however, has estimated the shape of the dose-response curve and incorporated such an estimate in potency estimation. In this manuscript, a measure of tumorigenic potency is proposed that utilizes the estimated shape of the dose-response relationship, in addition to estimated dose effects, in order to rank chemicals on the basis of carcinogenic risk. Comparison of this new measure to that of Sawyer et al. is done using a large database of animal carcinogenicity experiments from the National Cancer Institute and the National Toxicology Program.

Animals↗
PubMed1993

An index of tumorigenic potency.

A new index of tumorigenic potency is derived using a survival-adjusted quantal response estimator given by Bailer and Portier (1988, Biometrics 44, 417-431). The small-sample bias and mean squared error properties of this estimator are explored using computer simulations of animal carcinogenicity experiments and are compared to the characteristics of the TD50, an estimator proposed by Sawyer et al. (1984, Biometrics 40, 27-40). It is observed that this new index tends to have smaller bias and mean squared error relative to the TD50 over varying shapes of the tumor onset distribution, levels of tumor lethality, and levels of treatment lethality.

Animals↗
PubMed1990

A note on fitting one-compartment models: non-linear least squares versus linear least squares using transformed data.

Drug concentrations in one-compartment systems are frequently modeled using a single exponential function. Two methods of estimation are commonly used for determining the parameters of such a model. In the first method, non-linear least-squares regression is used to calculate the parameters. In the second method, the data are first transformed by a logarithmic function, and then the log-concentration data are fit using linear least-squares regression. The assumptions for fitting these models are discussed with special emphasis on which data points are most influential in determining parameter values. The similarities between fitting a linear regression model to the log-concentration data and fitting a weighted regression model to the original data are noted. An example is presented that illustrates the differences in fitting a model to the log-transformed data versus fitting unweighted and weighted models to the original-scale data.

Animals↗
PubMed1990

Estimating integrals using quadrature methods with an application in pharmacokinetics.

The estimation of integrals using numerical quadrature is common in many biological studies. For instance, in biopharmaceutical research the area under curves is a useful quantity in deriving pharmacokinetic parameters and in providing a surrogate measure of the total dose of a compound at a particular site. In this paper, statistical issues as separate from numerical issues are considered in choosing a quadrature rule. The class of Newton-Côtes numerical quadrature procedures is examined from the perspective of minimizing mean squared error (MSE). The MSE are examined for a variety of functions commonly encountered in pharmacokinetics. It is seen that the simplest Newton-Côtes procedure, the trapezoidal rule, frequently provides minimum MSE for a variety of concentration-time shapes and under a variety of response variance conditions. A biopharmaceutical example is presented to illustrate these considerations.

Animals↗
PubMed1989

Optimal design allocations for estimating area under curves for studies employing destructive sampling.

Optimal allocations of experimental resources for the estimation of integrals is considered for experiments that use destructive sampling. Given a set of sampling times, a minimum mean square error rule is given for the allotment of fixed experimental resources to the independent variable. The results are seen to be functionally dependent upon the pattern of underlying variability assumed in the model and upon the quadrature rule used to estimate the integral. Extensions to other optimality criteria, including a minimum mean absolute deviation criterion, and to cases involving multiple treatment groups, are also noted.

Models, Biological↗
PubMed1989

Testing for increased carcinogenicity using a survival-adjusted quantal response test.

The linear trend test in proportions is frequently used to analyze the results of animal carcinogenicity experiments. This test has two major advantages over other frequently used tests; it is easily understood and it is simple to calculate. This test, however, fails to correct for treatment-related differences in survival across the experimental groups. A test which is a simple modification of the linear trend test in proportions and which has the same advantages is proposed to correct for differences in survival. The results of this modified test are compared to those of the linear trend test in proportions, the incidental tumor test, the logistic regression score test, the life table test, and the truncated trend test using information on the incidence of combined alveolar/bronchiolar adenomas or carcinomas in female B6C3F1 mice exposed to vinylcyclohexene diepoxide.

Adenoma↗
PubMed1989

Two-stage models of tumor incidence for historical control animals in the National Toxicology Program's carcinogenicity experiments.

The tumor incidence rate is modeled for various tumors in a database of control animals [Fischer 344 rats and (C57BL/6 x C3H)F1 mice] originally developed by the national Toxicology Program and recently augmented to include additional sacrifice data by Portier et al. (1986). These rates are assumed to follow a clonal two-stage model of carcinogenesis where cells in the various tissues are allowed to be in one of three states arbitrarily defined as a "normal" state, an "initiated" state, and a "tumor present" state. The parameters of this clonal two-stage model have a direct interpretation with regard to the mechanism of action and in some cases may suggest a common mechanism for various tumors in the different sex/species groups. Also, the risk of dying (from all causes) in tumor-bearing animals is compared to the risk of dying in non-tumor-bearing animals via estimates of relative risk. In general, it was found that the risk of dying was elevated for most tumors. The purpose of this analysis is to provide estimates of baseline tumor rates and relative risks, which are useful in the design and analysis of future carcinogenicity experiments.

Animals↗