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Biomedical subjects

D G Hoel

Publications and source records attributed to D G Hoel.

At least 55 records · Page 3Linked to original sources
PubMed1990

Biologically based models for risk assessment.

The modelling problems associated with the estimation of risks from long-term chemical exposures at low dose levels represent a statistical and mathematical challenge with special relevance to environmental research. Determining an adequate model for estimating the relationship between dose and response is critical to reducing potential bias in the risk estimation process. This paper discusses the various assumptions and models used in carcinogenic risk assessment. The emphasis is on our ability to accurately determine the magnitude of the carcinogenic risk, the shape of the dose-response relationship and the overall variability of the risk estimates.

Animals↗
PubMed1989

Metabolite-based internal doses used in a risk assessment of benzene.

Risk assessments of benzene have been based upon both human and animal studies. In this paper, metabolite information is used to construct an internal dose (a surrogate of the biologically effective dose) for a given administered dose. The relationship between the administered dose and this internal dose is nonlinear and is well described by a Michaelis-Menten function. The administered doses from the National Toxicology Program's rodent carcinogenicity study of benzene are transformed into internal doses, and these internal doses are used in conjunction with a multistage model to compare previous estimated virtually safe doses (VSD) associated with small added health risks. The ratio of VSD for the administered dose risk assessment to the VSD from the internal dose risk assessment was approximately 1.0 for the F344/N rats and ranged from 2.5 to 5.0 for B6C3F1 mice in the National Toxicology Program study. For an occupational exposure of 1 ppm, a risk estimate of 0.7 excess cancers/1000 exposed with an upper bound of 3.5/1000 was obtained for a total metabolite internal dose risk assessment. Risk estimates based upon internal doses constructed from levels of the toxic metabolites of benzene are also presented. The implication of a dose-rate study of benzene metabolism for risk assessment is discussed, and finally, suggestions for better characterization of the dose-response function for benzene are provided.

Administration, Oral↗
PubMed1988

Exploring relationships between mutagenic and carcinogenic potencies.

Salmonella mutagenic and rodent carcinogenic potencies are calculated for 112 compounds recently studied by the U.S. National Toxicology Program. 28 of the 112 compounds are seen to exhibit simultaneous non-zero mutagenic and carcinogenic potencies. These are combined with an earlier list of mutagenic and carcinogenic compounds (McCann et al., 1988) in order to study possible trends in the data. A significant positive correlation is exhibited between mutagenic and carcinogenic potencies in the combined data, although the observed scatter is too great for the overall result to be predictive. Classification by chemical class further indicates positive correlations near one for chemicals classified as nitroaromatic and related compounds. Patterns in mutagenic and carcinogenic potency over time are also examined. Mean potencies of recently-studied compounds are seen to trend lower than those of compounds studied 10 or more years ago.

Animals↗
PubMed1988

The impact of toxicity on carcinogenicity studies: implications for risk assessment.

This paper explores the inter-relationship between toxicity, genotoxicity, and carcinogenicity in laboratory rodents. To our knowledge this is the first attempt to integrate these factors and evaluate their implications for the process of risk assessment. The evaluation is based on information obtained from 2-year laboratory-animal studies involving 99 chemicals. The data suggest that only seven of the 53 positive carcinogenicity studies exhibited the types of target organ toxicity that could have been the cause of all observed carcinogenic effects. Furthermore, no apparent difference in mutagenicity as measured by the Ames Salmonella assay was observed between 'high dose only' carcinogens and the entire set of carcinogens. These findings suggest that the number of chemical carcinogens that we can identify solely through rodent studies as being potential tumor inducers through some indirect mechanism is small. Generally speaking, the identification of histopathological effects is not sufficient in itself for justifying mechanistic assumptions, and supplemental biological information will be necessary to reach definitive conclusions.

Animals↗
PubMed1988

A theoretical study of the effect of methylation or ethylation at O6-guanine in the structure and energy of DNA double strands.

Quantum and molecular mechanical calculations were employed to examine the effect on binding energies and structure of methylation and ethylation at O6-guanine in double-stranded DNA. Ab initio quantum chemical calculations (STO-3G, 3-21G) were initially used to pseudo-optimize the structure of the 9-methyl derivative of O6-methylguanine. The distal orientation for the O6-methyl group was found to be lower in energy than the proximal orientation. The geometry determined for the distal O6-methyl group was in agreement with recent X-ray work. These results were used in supplementary parameterization of the AMBER molecular mechanics force field necessary for the minimization of DNA double strands containing O6-methylguanosine. Resulting calculations with AMBER on two 5-mer DNA sequences containing the promutagenic G(GM)A subsequence showed that the proximal orientation, while higher in energy in the isolated molecule, is both less disruptive to the DNA double helix and more stable than the distal orientation. Binding energies and degree of destabilization upon methylation were found to be functions of the adjacent bases around a GGA subsequence. Sequence-dependent destabilization could play a role in the repair of alkylated bases. Quantum and molecular mechanics calculations indicate that the O6-methyl and O6-ethylguanines behave energetically in a very similar manner. These calculations suggest that the necessity for the different repair mechanisms for methylation and ethylation lesions cannot be simply explained by energy differences or observed structural differences.

Alkylation↗
PubMed1987

Issues concerning the estimation of the TD50.

The TD50 (or tumorigenic dose rate 50) is a generally accepted measure of the carcinogenic potency of a chemical in a particular strain of animal. This paper discusses error in the estimation of the TD50 caused by intercurrent mortality and error resulting from consideration of only significant TD50's. Using computer simulations, we found that treatment-related toxicity had only a small effect on estimating the TD50, with errors seldom exceeding 5%. The TD50 is sensitive to changes in tumor lethality with errors ranging to as high as 50%. Many of these errors were significantly different from zero and the results suggest that potency estimation could be improved by basing the estimates upon the tumor incidence rate rather than upon the tumor death rate when an estimate of tumor lethality is obtainable.

Animals↗
PubMed1987

Radiation risk estimation models.

Cancer risk models and their relationship to ionizing radiation are discussed. There are many model assumptions and risk factors that have a large quantitative impact on the cancer risk estimates. Other health end points such as mental retardation may be an even more serious risk than cancer for those with in utero exposures.

Animals↗
PubMed1987

Cancer risk models for ionizing radiation.

Risk estimation in radiation carcinogenesis depends primarily on epidemiological data and hazard rate models. The A-bomb survivors follow-up provides information on the complexity of this process. Several hazard rate models are briefly discussed and illustrated using the A-bomb experience.

Dose-Response Relationship, Radiation↗
PubMed1987

Altitude, radiation, and mortality from cancer and heart disease.

The variation in background radiation levels is an important source of information for estimating human risks associated with low-level exposure to ionizing radiation. Several studies conducted in the United States, correlating mortality rates for cancer with estimated background radiation levels, found an unexpected inverse relationship. Such results have been interpreted as suggesting that low levels of ionizing radiation may actually confer some benefit. An environmental factor strongly correlated with background radiation is altitude. Since there are important physiological adaptations associated with breathing thinner air, such changes may themselves influence risk. We therefore fit models that simultaneously incorporated altitude and background radiation as predictors of mortality. The negative correlations with background radiation seen for mortality from arteriosclerotic heart disease and cancers of the lung, the intestine, and the breast disappeared or became positive once altitude was included in the models. By contrast, the significant negative correlations with altitude persisted with adjustment for radiation. Interpretation of these results is problematic, but recent evidence implicating reactive forms of oxygen in carcinogenesis and atherosclerosis may be relevant. We conclude that the cancer correlational studies carried out in the United States using vital statistics data do not in themselves demonstrate a lack of carcinogenic effect of low radiation levels, and that reduced oxygen pressure of inspired air may be protective against certain causes of death.

Altitude↗
PubMed1986

Statistical modeling of animal bioassay data with variable dosing regimens: example--vinyl chloride.

We consider animal bioassay experiments with variable dosing regimens in which groups of animals are dosed beginning at different ages and for varying durations. Two response models are discussed and then applied to data from an experiment on vinyl chloride exposure of F-344 rats, B6C3F1 and Swiss CD-1 mice, and Syrian Golden hamsters. The multistage model of Armitage and Doll, as extended by Whittemore, Day and Brown, and Crump and Howe, is used to estimate the dose effect on the ordered stages of tumor development. The data for all endpoints and species/strains examined consistently indicate a predominant effect on the first stage, suggesting that vinyl chloride is primarily a tumor initiator. This is consistent with evidence from two-stage experiments on this chemical. The second response model, new to this article, adjusts for survival nonparametrically. It is used to test for an age difference in susceptibility, to evaluate alternative exposure durations, and to compare the effectiveness of alternative dosing regimens for detecting carcinogenicity.

Animals↗
PubMed1986

Age-specific models of mortality and tumor onset for historical control animals in the National Toxicology Program's carcinogenicity experiments.

This paper models general survival and the distribution of tumor onset times for various tumors in the data base of control animals developed by the National Toxicology Program. For general survival, a modified Weibull model is shown to give an adequate fit for both Fischer 344 rats and C57BL/6 X C3H F1, mice. In addition, data from control animals in a lifetime study of asbestos are used to support the extension of these survival curves beyond 2 years in Fischer rats. The distributions of tumor onset times are modeled using a two-parameter Weibull model. For many common tumor types, this model yielded a very good fit to the data. Finally, a summary measure of the contribution of a tumor to mortality is given.

Age Factors↗
PubMed1985

Some tautologous aspects of the comparison of carcinogenic potency in rats and mice.

In risk estimation, the results of rodent carcinogenesis experiments are often used to quantitatively predict effects in man. The justification for this approach has in large part been dependent upon the good correlation of carcinogenic potency found between mice and rats over large numbers of test chemicals. Using the data base of chemicals tested by the NCI Bioassay Program, we observe that there is a very high correlation of the maximum doses tested (max-d) for rats and mice on a milligram per kilogram body weight per day basis. Next we show that the calculated carcinogenic potency (b-defined in the paper) is restricted to an approximately 30-fold range surrounding log(2)/max-d, which has a biological as well as a statistical basis. Since the max-d's for the set of NCI test chemicals vary over many orders of magnitude, it necessarily follows statistically that the carcinogenic potencies will be highly correlated. This "artifact" of potency estimation does not imply that there is no basis for extrapolating animal results to man. It does suggest, however, that the interpretation of correlation studies of carcinogenic potency needs much further thought.

Animals↗
PubMed1985

Use of historical controls for animal experiments.

Statistical methods for the use of historical control data in testing for a trend in proportions in carcinogenicity rodent bioassays are reviewed. Asymptotic properties of the Hoel-Yanagawa exact conditional tests are developed and compared with the Tarone test. It is indicated that the Hoel-Yanagawa test is more powerful than the Tarone test. These tests depend on the beta-binomial parameters which are estimated from historical data. The goodness of fit of beta-binomial distributions to historical data is illustrated by application to the historical control database in the National Toxicology Program. Finally, sensitivities of the exact conditional test to the historical information is discussed and a conservative use of the test is considered.

Animals↗
PubMed1985

Epidemiology and the inference of cancer mechanisms.

Through the use of molecular methods and mathematical models, epidemiologists are contributing to the improved understanding of the mechanisms of cancer. Multistage models with their mechanistic basis have been useful in descriptions of initiator-promoter type behavior of some carcinogens as well as genetic predisposition to rare tumors and reproductive risk factors in breast cancer. The use of biochemical and molecular laboratory techniques on tissue and fluid samples should provide important information in the near future concerning the basic mechanisms of human cancer. The potential of these methods is not only to describe exposure to carcinogens but also to indicate various host factors and their relevance to the risk of cancer.

Carcinogens↗
PubMed1984

Design of animal carcinogenicity studies for goodness-of-fit of multistage models.

The effect of bioassay design changes on the variability of risk estimates in the experimental dose region is investigated. Three-dose designs with a control group and other "usual" designs utilizing 200 animals are studied in detail. Constraints on the minimum power of the linear trend test in proportions are used to eliminate designs with unacceptable power. An acceptable design region is compared to designs aimed at improving the low dose extrapolation. A group of designs acceptable for a range of objectives is proposed.

Animals↗
PubMed1984

Nonparametric estimation of the survival function when cause of death is uncertain.

A nonparametric estimator for the survival function, accommodating censored survival times and uncertainty in the assignment of cause of death, is proposed. For example, in a carcinogenicity experiment the data on each animal may consist of an observed age-at-death and some indication of the probability that the tumor type under study caused death. An estimator of the net survival function, for time-to-death due to the cause of interest, is developed. Under certain assumptions, the proposed estimator is consistent and asymptotically normally distributed. Monte Carlo simulations were used to compare this estimator with the Kaplan-Meier estimator. Forcing the cause of death to be specified with certainty, as required by the Kaplan-Meier estimator, may result in substantial biases.

Animals↗