Grantee Research Project Results
Final Report: Biologically-Based Dose-Response Models for Cancer Risk Assessment
EPA Grant Number: R824762Title: Biologically-Based Dose-Response Models for Cancer Risk Assessment
Investigators: Moolgavkar, Suresh H. , Luebeck, E. Georg
Institution: Fred Hutchinson Cancer Research Center
EPA Project Officer: Hahn, Intaek
Project Period: October 1, 1995 through September 30, 1998
Project Amount: $387,615
RFA: Human Health Risk Assessment (1995) RFA Text | Recipients Lists
Research Category: Human Health
Objective:
The focus of this research was the development of mathematical models of carcinogenesis, of the requisite statistical and computational tools for the analyses of experimental and epidemiological data using these models, and the investigation of dose-response relationships for risk assessment within the framework of the models.
Laboratory and epidemiological evidence leave little doubt that carcinogenesis is a multistage process. Furthermore, disruption of normal cell proliferation and differentiation are the sine qua non of the malignant state. Conversely, there is accumulating evidence that the kinetics of cell proliferation and differentiation in normal and premalignant cells are important in the carcinogenic process. Increases in cell division rates may lead to increase in the rate of critical mutational events, and an increase in cell division without a compensatory increase in differentiation or apoptosis leads to an increase in the size of critical target cell populations. These observations indicate that carcinogenesis involves successive genomic changes, each change resulting in further disruption of cellular kinetics, which, in turn, accelerates the acquisition of more mutations. It is these critical aspects of the process of carcinogenesis that were being modeled under the auspices of this grant.
Summary/Accomplishments (Outputs/Outcomes):
Statistical and computational methods were developed for analyses of two types of data. The first, derived from epidemiological studies and some experimental work, are data on the incidence of cancers of specific types in populations of humans and animals exposed to putative carcinogens. The crucial mathematical expression that must be derived for the analyses of such data sets is the hazard function. Examples of analyses conducted include the investigation of the joint effects of radon progeny and tobacco smoke in causing lung tumors in humans, and the investigation of the role of radon progeny in causing lung tumors in rats. The second type of data arises in initiation-promotion experiments, particularly in the rodent liver. Expressions for the number and size distribution of intermediate lesions on the pathway to malignancy were derived and used for analyses of initiation-promotion experiments in the rat liver. The fundamental goal of these analyses is to study the dependence of the rate of initiation and of the rates of cell division and apoptosis on the dose of the chemical agents of interest.
The developed methods were applied to the analyses of radiation-induced tumors arising in the cohort of A-bomb survivors at Hiroshima and Nagasaki. A two-stage stochastic model of carcinogenesis was used to analyze the incidence of cancers of the lung, stomach and colon in the cohort of atomic bomb survivors. The model was fitted assuming that acute exposure to radiation results in the creation of initiated cells that are added to the pool of cells that are being spontaneously initiated. In all cancers analyzed, with the exception of lung cancer in females, there was no evidence that radiation-induced initiation was dependent on age at exposure. In contrast, spontaneous initiation was dependent upon age at exposure in all cancers except stomach cancer among males. Because exposure to radiation in this cohort was instantaneous, age at exposure is perfectly correlated with birth cohort, and the dependence of spontaneous initiation on age at exposure is a reflection of the cohort effects seen in these cancers in Japan. Even without an age-at-exposure dependence of radiation-induced initiation, the two-stage model can explain the temporal behavior of the excess relative risk with age at exposure and time since exposure. In particular, the model predicts that excess relative risk is highest among those exposed as children. Moreover, since radiation-induced initiation is not higher among those exposed as children, the high excess relative risk among those exposed as children is not due to an inherently higher sensitivity to radiation. The biologically-based approach used for these analyses provides another perspective on the temporal behavior of risk after acute exposure to ionizing radiation.
The methods developed for analyses of intermediate foci were used to estimate rates of initiation (alteration to express the ATPase deficient phenotype) and of clonal growth of altered cells in an initiation promotion experiment in the livers of female Wistar rats. Diethylnitrosamine (DEN) was used as the initiating agent followed by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HCDD) as promoters. Two distinct versions of the stochastic model, called Model I and Model II, were fitted to the data. Model I made the assumption that, after the initial phase of acute initiation with DEN, background rates of initiation were equal in animals treated with DEN and controls that were not so treated. Model II, which fit the data substantially better than Model I, assumed that background rates of initiation were different in DEN-treated animals and animals not so treated, even after the acute phase of initiation was over. Both models indicate that the rates of cell division and apoptosis of altered cells are increased during TCDD treatment. In contrast, the rate of division remains more or less constant during treatment with HCDD, but the rate of apoptosis is decreased. The background rate of initiation during treatment with HCDD is equal to that in controls not administered promoters. With TCDD treatment, however, the rate of initiation estimated form the model is substantially increased over controls. The analysis also suggests that there is heterogeneity within foci of the rates of cell division, with cells on the surface of foci dividing faster than cells in the interior.
Journal Articles on this Report : 8 Displayed | Download in RIS Format
Other project views: | All 9 publications | 9 publications in selected types | All 8 journal articles |
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Dewanji A, Luebeck EG, Moolgavkar SH. A biologically-based model for the analysis of premalignant foci of arbitrary shape. Mathematical Biosciences 1996;135(1):55-68. |
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Gaylor DW, Moolgavkar SH, Krewski D, Goldstein LS. Recent bioassay results on coal tars and benzo(a)pyrene: implications for risk assessment. Regulatory Toxicology and Pharmacology 1998;28(2):178-179. |
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Heidenreich W, Luebeck KM, Moolgavkar SH. Some properties of the hazard function of the two-mutation clonal expansion model. Risk Analysis 1997;17(3):391-399. |
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Kai M, Luebeck KM, Moolgavkar SH. Analysis of solid cancer incidence among atomic bomb survivors using a two-stage model of carcinogenesis. Radiation Research 1997;148(4):348-358. |
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Luebeck KM, Moolgavkar SH. Biologically based cancer modelling. Drug and Chemical Toxicology 1996;19(3):221-243. |
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Moolgavkar SH, Luebeck EG, Buchmann A, Bock KW. Quantitative analysis of enzyme-altered foci in rats initiated with diethylnitrosamine and promoted with 2,3,7,8-tetrachlorodibenzo-p-dioxin or 1,2,3,4,6,7,8-heptachloro-p-dioxin. Toxicology and Applied Pharmacology 1996;138(1):31-42. |
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Moolgavkar SH. Stochastic cancer models: application to analyses of solid cancer incidence in the cohort of A-bomb survivors. Nuclear Energy 1997;36(6):447-451. |
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Moolgavkar SH. Comments on papers on U-shaped dose-response relationships for carcinogens. Human and Experimental Toxicology 1998;17(12):708-710. |
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Supplemental Keywords:
dose-response, susceptibility of children, radiation risk, epidemiology, mathematics., RFA, Health, Scientific Discipline, Health Risk Assessment, Genetics, Risk Assessments, Molecular Biology/Genetics, cancer risk, malignancy, cell biology, dose response, genotoxic, two mutation clonal expansion model, carcinogens, human exposure, cancer risk assessment, biologically based model, cell divisionProgress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.