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Biomedical subjects

D Hoel

Publications and source records attributed to D Hoel.

11 recordsLinked to original sources
PubMed1993

Ligand/receptor binding for 2,3,7,8-TCDD: implications for risk assessment.

There is renewed controversy regarding safe exposure levels for dioxin. At the heart of this controversy is the hypothesis that toxic effects of dioxin are receptor-mediated and therefore a "threshold" should exist below which no toxic effects can occur. Our research focuses on the ability of dioxin to alter protein levels in rodent livers. Established effects of exposure to dioxin are the induction of cytochrome P450-1A1 and P450-1A2 and a reduction in the maximal binding of the epidermal growth factor receptor in rat livers. An initiation-promotion protocol was used to study the effects of dioxin in female Sprague-Dawley rats. Animals were administered a single initiating dose of diethylnitrosamine followed by 16 biweekly gavage doses of 2,3,7,8-TCDD. Steady-state pharmacodynamic models were fit to these data assuming a combination of Hill kinetics and Michaelis-Menten kinetics. Two classes of models were developed which postulate two different mechanisms for the constitutive expression and TCDD-induced alterations in the levels of these proteins. The results are consistent with models which follow proportionate response in the low-dose region (no threshold) and with models which allow for a low-dose threshold. In all cases studied, the best fitting model exhibited no "threshold" for the effects of TCDD on the modulation of these proteins. The finding is consistent with the knowledge that for some receptor-mediated responses, there is a proportional relationship between receptor occupancy and biological response, even at low ligand concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Perspective and overview of the concepts and value of hazard identification as the initial phase of risk assessment for cancer and human health.

The identification of potential human health hazards stems from the obvious need to prevent, avoid, reduce, and eliminate exposure to hazardous agents, mixtures of agents, or exposure circumstances. The first step in the risk assessment process centers on determining if a hazard exists. The following strategies are used for this purpose: (i) epidemiologic investigations, (ii) long-term chemical toxicology and carcinogenesis studies on laboratory animals, (ii) shorter-term in vivo and in vitro assays, and (iv) physicochemical structure-activity relationships. Indicator 1 is the most relevant and reliable if adequate data are available; indicator 2 is the most valid and useful alternative for human experience; indicator 3 allows certain toxicologic end points to be identified, but generally needs confirmatory and supportive information; and indicator 4 has made gains in the area of predictivity. The advantages and limitations of each are given. The magnitude of the overall cancer hazard identification effort and a likelihood number of eventual chemical carcinogens have also been estimated.

Animals↗
PubMed1991

Is brain cancer mortality increasing in industrial countries?

This paper analyzes age-specific trends in brain and other central nervous system cancer mortality from 1968 to 1987 in several major industrial countries. It also examines changes in the use of diagnostic confirmation technology and trends in incidence in the U.S. National Cancer Institute, Surveillance, Epidemiology, and End Results (SEER) program from 1973 to 1987 to estimate the influence of diagnostic factors on recent mortality trends. Other sources of error have not been evaluated in this paper. Age-specific analyses of brain and other nervous system cancer mortality show drastic increases in persons ages 75-84 and consistent increases in younger age groups in most countries, although mortality declined in the U.S. in persons 0-24 by 2% annually. In the SEER program, brain cancer incidence increased significantly by 2%, 1%, and 5% annually in persons aged 0-44, 65-74, and 75-84, respectively. Throughout this time period, microscopic or radiographic confirmation occurred in at least 96% of all incident cases of brain and other central nervous system cancers diagnosed before death, with older persons receiving consistently more radiographic tests than younger persons. Changes in diagnoses across populations and over time are unlikely to account completely for these increasing trends which are occurring simultaneously in both males and females in major industrial countries. Additional studies need to be conducted, to exclude artifacts, to assist health care planners in anticipating treatment demands, and to detect preventable causes of these changing trends.

Adult↗
PubMed1990

International trends in cancer mortality in France, West Germany, Italy, Japan, England and Wales, and the USA.

Age-specific worldwide trends in cancer mortality were reviewed, with emphasis on cancer sites where increases have been reported in the USA. Cancer rates vary by factors as high as 30 between all countries, and 5-fold within and between industrialised countries. In Italy, Japan, Federal Republic of Germany, England and Wales, and the USA, patterns of cancer mortality have shifted uniformly over the past two decades. Stomach cancer continues to decline, while brain and other central-nervous-system cancer, breast cancer, multiple myeloma, kidney cancer, non-Hodgkin lymphoma, and melanoma have increased in persons aged 55 and older. Cancer of the lung is starting to decline for men under age 85 and women under age 60 in England and Wales and men under age 45 in the USA, but is still rising for men and women in other countries. All forms of cancer are increasing in persons over age 54 except lung and stomach (which together comprise between 20% and 43% of all cancer in males in these countries). Studies of the quality of ascertainment and enumeration indicate that these increases are not attributable solely to diagnostic artifacts or to increased access to health care, although both these factors may be involved. These recorded increases in cancer should be assessed in greater detail to provide better projections of health care needs and to identify causal factors that may be controlled. The changes in cancer other than lung are so great and rapid that their causes demand intensive investigation.

Adult↗
PubMed1990

Is brain cancer mortality increasing in industrial countries?

This paper analyzes recent age-specific trends in brain and other central nervous system cancer mortality from 1968 to 1986-1987 in the United States, United Kingdom, Italy, France, and West Germany. It also examines changes in the use of diagnostic confirmation technology in the U.S. SEER program from 1973 to 1987 to estimate the influence of such factors on recent mortality trends. Other sources of error have not been evaluated in this paper. In the United States and Sweden, deaths due to brain and other central nervous system cancer, adjusted to the overall population, are unchanging. However, age-specific analyses of brain and other nervous system cancer in six major industrial countries show markedly different trends at different age groups, with drastic increases in brain tumor rates in the old: rates doubled in persons ages 75 to 84. In the United States, microscopic or radiographic confirmation occurred throughout this time period in 96% of all incident cases of brain and other central nervous system cancers diagnosed before death in the SEER program, with older persons receiving consistently more radiographic tests than younger persons. The use of diagnostic technology may change over time and across populations, but it is not known to what extent it accounts for these increasing trends, which require careful additional study.

Adolescent↗
PubMed1986

An empirical comparison of methods used to estimate carcinogenic potency in long-term animal bioassays: lifetable vs summary incidence data.

Two methods for estimating carcinogenic potency from animal carcinogenesis bioassays (TD50-defined in the paper) are compared, one based on lifetable data and one based on summary incidence data. The lifetable analysis adjusts for the differential effects of toxicity among dose groups and for differences in the time pattern of tumor incidence, while summary incidence analysis does not. However, summary data are all that are usually available in the published results of animal cancer tests. Using NCI bioassay results which provide full lifetable data, we compare lifetable and summary estimates of potency and their statistical significance as well as the estimated shape of the dose-response curve. There is substantial agreement between these methods of analysis in terms of potency estimation, although lifetable estimates are usually more potent. But, there are some notable differences in the estimated shape of the dose-response curve, suggesting that both target site selection and method of analysis play an important role in risk estimation.

Actuarial Analysis↗
PubMed1983

Optimal design of the chronic animal bioassay.

Optimal experimental designs for carcinogenicity bioassays conducted for the assessment of risks associated with exposure to environmental chemicals are derived. For our purposes, an optimal experimental design is a design that minimizes the mean-squared error of the maximum likelihood estimate of the virtually safe dose from the Armitage-Doll multistage model and maintains a high power for the detection of increased carcinogenic response. Three- and four-dose designs (including control as one of the doses) are discussed for a variety of dose response patterns. Monte Carlo simulation techniques are used to estimate the power and mean-squared error for small samples sizes. Two forms of the multistage model are used to estimate the virtually safe dose: the linear model and the linear-quadratic model. The optimal designs for fitting the linear model used a control group and a group administered the maximum tolerated dose, with about 50% of the animals at each dose. The three- and four-dose optimal designs when fitting the linear-quadratic model were found to be equivalent. However, after considering several biological issues, including overt toxicity, the optimal four-dose designs would use between 150 and 300 animals, with 50 to 60 animals in the control group, and 40 to 60 animals in the group administered the maximum tolerated dose. One-third of the remaining animals would be administered a dose between 10 and 30% of the maximum tolerated dose, and two-thirds of the remaining animals would be administered 50% of the maximum tolerated dose.

Animals↗
PubMed1983

Low-dose-rate extrapolation using the multistage model.

The distribution of the maximum likelihood estimates of virtually safe levels of exposure to environmental chemicals is derived by using large-sample theory and Monte Carlo simulation according to the Armitage-Doll multistage model. Using historical dose-response we develop a set of 33 two-stage models upon which we base our conclusions. The large-sample distributions of the virtually safe dose are normal for cases in which the multistage-model parameters have nonzero expectation, and are skewed in other cases. The large-sample theory does not provide a good approximation of the distribution observed for small bioassays when Monte Carlo simulation is used. The constrained nature of the multistage-model parameters leads to bimodal distributions for small bioassays. The two modes are the direct result of estimating the linear parameter in the multistage model; the lower mode results from estimating this parameter to be nonzero, and the upper mode from estimating it to be zero. The results of this research emphasize the need for incorporation of the biological theory in the model-selection process.

Biological Assay↗