Air pollution and mortality.
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Air Pollution↗
Biomedical subjects
S H Moolgavkar
Publications and source records attributed to S H Moolgavkar.
Simulating the process of malignant transformation.
A computationally efficient method for the simulation of carcinogenesis is presented. The underlying model for the process is the two-mutation clonal expansion model with explicit consideration of stochastic growth of malignant tumors. The usual likelihood-based methods of analysis ignore the growth kinetics of malignant tumors. The effect of this oversight on estimation of parameters is explored by simulation.
Animals↗
Biological models of carcinogenesis and quantitative cancer risk assessment.
Biologically-based models of carcinogenesis were originally developed to explain certain quantitative phenomena associated with carcinogenesis, and to provide a framework within which questions regarding the process could be addressed. Some limitations in the use of these models for quantitative cancer risk assessment are discussed.
Animals↗
Allelic instability in mitosis: a unified model for dominant disorders.
Recent findings indicate that tandemly repeated triplet sequences in certain disease-causing human genes may render these genes highly unstable not only in meiosis but also in mitosis. Typically, a dominant mutation arises upon expansion in the number of these repeated elements. We have considered how mitotic instability of this sort might affect both phenotypic expression and allele transmission. A model based on these considerations leads to the following predictions: (i) Phenotypic severity among individuals who inherit an unstable allele should be highly variable due to stochastic variation in the stage of its earliest mutagenic expansion. (ii) Strikingly increased severity or decreased age of onset in some offspring should arise because of parental germ-line mosaicism for an expanded or mutant allele. (iii) The magnitude of genetic anticipation should be more strongly correlated with paternal than with maternal age at the time of conception. (iv) Given a child born with a severe phenotype, the recurrence risk for a second severely affected child should be significantly elevated. (v) The severity of phenotype in a child should be positively correlated with that in a parent. Available data on fragile X syndrome, Huntington disease, and myotonic dystrophy are shown to be consistent with the model, and implications for an understanding of achondroplasia and other dominant disorders are discussed.
Alleles↗
Cell proliferation and carcinogenesis models: general principles with illustrations from the rodent liver system.
Rates of cell proliferation, cell death, and cell differentiation affect the risk of cancer profoundly. An increase in cell proliferation rates leads to an increase in mutation rates per unit of time, which, in turn, leads to an increase in the risk of cancer. An increase in cell division rates relative to death or differentiation rates may lead to an increase in the population of critical target cells, which, again, leads to an increase in cancer risk. These fundamental principles are well illustrated by the rodent liver model for carcinogenesis. In this paper I briefly discuss some of the consequences of incorporating cell proliferation kinetics into quantitative models of cancer risk assessment. Consideration of cell kinetics can shed light on apparently paradoxical observations, such as the observation that the administration of two different promoters may lead to the same volume fraction in the rodent liver, with one promoter giving rise to a large number of small foci and the other to a small number of large foci. Another observation that can be illuminated by a consideration of cellular proliferation kinetics is the phenomenon of the inverse dose-rate effect. It has been observed with exposure to high LET radiation and to certain chemicals that fractionation of a given total dose of the agent leads to an increased life-time probability of tumor. A biological explanation of this finding can be given in terms of the effect of the agent on cell proliferation kinetics.
Animals↗
Radon, cigarette smoke, and lung cancer: a re-analysis of the Colorado Plateau uranium miners' data.
Much of our knowledge regarding the interaction of radon and tobacco smoke in the etiology of human lung cancer derives from studies of uranium miners. In this article, we present a re-analysis of lung cancer mortality in the Colorado Plateau miners' cohort within the framework of the two-mutation clonal expansion model of carcinogenesis. This analysis takes into account the patterns of exposure to radon and cigarette smoke experienced by individuals in the cohort. A simultaneous re-analysis of the British doctors' cohort indicated that those model parameters relating to the effects of tobacco were comparable in the two data sets. We found no evidence of interaction between radon and tobacco smoke with respect to their joint effect on the first or second stage mutation rates or on the rate of proliferation of initiated cells. The age-specific relative risks associated with joint exposure to radon and cigarette smoke, however, were supra-additive but submultiplicative. The analysis also confirmed that fractionation of radon exposures leads to higher lung cancer risks. Finally, we present some estimates of lung cancer risk from environmental radon exposure for non-smokers and smokers.
Adult↗
Multistage carcinogenesis: population-based model for colon cancer.
BACKGROUND: Recent laboratory work and previous models suggest that multiple mutations are associated with the development of colon cancer. PURPOSE AND METHODS: To estimate the number of mutations required for colon carcinogenesis, we used likelihood analysis to obtain the best fit between mathematical models postulating different numbers of rate-limiting events and data on incidence rates of colon cancer in two human populations--the general population of Birmingham, England, from 1968 to 1972 and patients with familial adenomatous polyposis (FAP) diagnosed at Saint Mark's Hospital, London, England, between 1925 and 1965. The Armitage-Doll model and two- and three-mutation models that explicitly incorporated cell proliferation kinetics were used. RESULTS: When cell kinetics were considered, models postulating either two or three rate-limiting events described the incidence rates of colon cancer equally well in both human populations. A comparison of the incidence rate of colon cancer in the general population with that in patients with polyposis suggests that a mutation at the FAP gene locus is not one of the rate-limiting events in colon carcinogenesis. CONCLUSIONS: Compared with the two-mutation model, the three-mutation model was more consistent with the number of mutations reported to date in colon cancer and with mutation rates measured in the laboratory. IMPLICATIONS: A mutation at the FAP locus may not be a rate-limiting step but may act indirectly by stimulating the proliferation of stem cells. Thus, the development of colon cancer in patients with FAP does not appear to fit the retinoblastoma paradigm.
Adenomatous Polyposis Coli↗
Risk assessment of non-genotoxic carcinogens.
Rates of cell proliferation, cell death, and cell differentiation affect the risk of cancer profoundly. An increase in cell proliferation rates leads to an increase in mutation rates per unit of time, which, in turn, leads to an increase in the risk of cancer. An increase in cell division rates relative to death or differentiation rates may lead to an increase in the population of critical target cells, which, again, leads to an increase in cancer risk. These fundamental principles are well illustrated by the rodent liver model for carcinogenesis. In this paper, we shall briefly discuss some of the consequences of incorporating cell proliferation kinetics into quantitative models of cancer risk assessment. Consideration of cell kinetics can shed light on apparently paradoxical observations such as, e.g. the observation that the administration of two different promoters may lead to the same volume fraction in the rodent liver, with one promoter giving rise to a large number of small foci, and the other to a small number of large foci. Some consequences of explicitly considering cell proliferation kinetics in malignant foci are briefly discussed.
Animals↗
Interpretation of labeling indices in the presence of cell death.
A simple method is presented for the analysis of data on labeling indices in populations of cells undergoing division and apoptosis. The method is applicable to continuous, osmotic pump labeling experiments, and provides estimates of cell division rates. Cell replication kinetics play an important role in carcinogenesis, and the interpretation presented here should help in the incorporation of data on labeling indices into quantitative models for cancer risk assessment.
Animals↗
Carcinogenesis models: an overview.
Biologically based mathematical models of the process of carcinogenesis are not only an essential part of a rational approach to quantitative cancer risk assessment, but also raise fundamental questions about the nature of the events leading to malignancy. In this paper two such models are reviewed. The first is the multistage model proposed by Armitage and Doll in the 1950s. The larger part of the paper is devoted to a discussion of the two-mutation model proposed by Moolgavkar and colleagues. This model is a generalization of the idea of recessive oncogenesis proposed by Knudson, and has been shown to be consistent with a large body of epidemiological and experimental data. The usefulness of the model is illustrated by analysis of a large experimental data set in which rats exposed to radon develop malignant lung tumors.
Animals↗
Two-mutation model for carcinogenesis: joint analysis of premalignant and malignant lesions.
A model for carcinogenesis that postulates two rate-limiting events for malignant transformation is a generalization of the recessive oncogenesis hypothesis, according to which inactivation of homologous tumor suppressor genes leads to cancer. This model has been shown to be consistent with a large body of epidemiologic and experimental data and has recently been used for the analysis of altered hepatic foci in rodents. These foci are considered to be premalignant lesions. In this paper the necessary mathematics for the joint analysis of premalignant and malignant lesions are developed within the framework of this model.
Animals↗
Effects of polychlorinated biphenyls in rat liver: quantitative analysis of enzyme-altered foci.
The promotional effect of various polychlorinated biphenyls and phenobarbital on enzyme-altered lesions in the rat liver was quantified within the framework of the two-stage carcinogenesis model of Moolgavkar and colleagues. The experiment analyzed here followed an initiation-promotion protocol in which female Wistar rats were initiated with diethylnitrosamine (DEN) at 10 mg/kg body wt for 10 days followed by a 8-week period of promoter treatment with various cytochrome P450 isoenzyme inducing and noninducing compounds. This analysis included 4-monochlorobiphenyl, 2,2',4,5'-tetrachlorobiphenyl, 3,3',4,4'-tetrachlorobiphenyl and 3-methylcholanthrene, all administered at 150 mumol/kg body wt, and phenobarbital which was administered continuously in the diet at 0.05% until termination. Animals were killed either 1 or 9 weeks after the end of treatment and their livers were examined for enzyme histological alterations. Focal transections were classified as falling into three phenotypic categories: ATPase dominant, GGT dominant, or ATPase plus GGT (coextensive). A quantitative method was used to analyze the data consisting of the number and sizes of the focal transections. The number of cells altered by the DEN treatment and cell kinetic parameters measuring the promotional effect of the various compounds were estimated. On the basis of these estimates, we computed the number of nonextinct altered foci and their volume fraction as functions of time. We found that foci exhibiting the coextensive phenotype respond most efficiently to promoter treatment, while GGT dominant foci respond weakly to all the promoters with the exception of 3-MC. For phenobarbital, we observed a significant slowing of focal cell proliferation over time.
Adenosine Triphosphatases↗
Stochastic analysis of intermediate lesions in carcinogenesis experiments.
In many animal model systems for carcinogenesis, well characterized putative premalignant lesions are observed. A much studied example is provided by the enzyme altered foci in rodent hepatocarcinogenesis experiments. In a recent paper, we proposed a method for the quantitative analysis of such premalignant lesions. The model used in that paper assumed that the mean growth of premalignant clones is exponential. However, it has been suggested that such a model is oversimplified. In this paper, we relax the assumption of exponential mean growth. The new model contains one extra parameter that measures departures from exponentiality. Use of the model is illustrated by analysis of ATPase deficient foci in the liver of rats given NNM (N-nitrosomorpholine) in their drinking water. The analysis suggests that the clonal growth of altered cells is significantly accelerated (superexponential) for nontoxic doses of NNM. Finally, the hazard function of the two-mutation model for carcinogenesis is briefly discussed under nonexponential (mean) growth of intermediate cells.
Adenosine Triphosphatases↗
A population perspective on multistage carcinogenesis.
The concept of multistage carcinogenesis is one of the central dogmas of cancer research today. Recent laboratory work suggests that many specific genetic changes are associated with carcinogenesis. At the same time, there is increasing evidence that cell proliferation kinetics are important in carcinogenesis. In 1971, Knudson proposed his now celebrated two-mutation model for embryonal tumors. In fact, a two-mutation model that explicitly considers cell kinetics is the most parsimonious model consistent with the incidence of both childhood and adult cancer in human populations. This model has been known to be consistent, as well, with other epidemiologic and experimental data. But can such a model be reconciled with the laboratory evidence suggesting that many genetic alterations are required for malignant transformation? In this paper, I examine multistage carcinogenesis from the population perspective. Can cancer incidence data in populations provide some insight into the number and nature of stages involved in malignant transformation? I focus attention on carcinoma of the colon because of the considerable amount of information that is now available on the genetics of these tumors. Also, as is the case with retinoblastoma, colon cancer occurs in sporadic and dominantly inherited forms. A comparison of the incidence of these two forms of colon cancer suggests that mutation at the familial adenomatous polyposis (FAP) locus is not necessary for colon cancer, and that inheritance of the gene for FAP is not equivalent to inheriting one of the essential steps on the pathway to colon cancer. Thus, colon cancer does not follow the retinoblastoma paradigm. The incidence of colon cancer in the general population and among polyposis subjects is consistent with two or three mutations on the pathway to malignancy. A three-mutation model is more consistent with the genetic alterations observed in colon carcinogenesis. I present and discuss a working model for colon cancer.
Adenomatous Polyposis Coli↗
The role of somatic mutations and cell replication kinetics in quantitative cancer risk assessment.
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Adenosine Triphosphatases↗
Stochastic description of initiation and promotion in experimental carcinogenesis.
Hepatocarcinogens are known to give rise to enzyme altered foci (EAF) in the liver. Since EAF are regarded as intermediate on the pathway to cancer, the promoting effect of chemical compounds on their growth is of critical importance in the assessment of the cancer risk. Using a stochastic description based on the two-mutation model we outline a quantitative analysis of EAF in the rat liver.
Adenosine Triphosphatases↗
Quantitative analysis of enzyme-altered foci in rat hepatocarcinogenesis experiments--I. Single agent regimen.
Considerable recent attention has focused on the quantitative analysis of enzyme-altered foci in rodent hepatocarcinogenesis experiments. These foci are believed to represent clones of premalignant cells. A method is presented for the quantitative analysis of these foci that takes into account both the total number of focal transections observed in each liver cross-section and the size distribution of these transections. The method, which has a natural interpretation within the framework of a two-mutation model for carcinogenesis, yields estimates of rates of initiation and of growth rates of enzyme-altered foci as functions of dose of the agent under consideration. Definitions of initiation and promotion potencies are proposed. The method is illustrated by application to an experiment in which rats were administered N-nitrosomorpholine at various concentrations in their drinking water.
Adenosine Triphosphatases↗