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S H Moolgavkar

Publications and source records attributed to S H Moolgavkar.

At least 37 records · Page 2Linked to original sources
PubMed1999

Quantitative assessment of the risk of lung cancer associated with occupational exposure to refractory ceramic fibers.

We present the results of a quantitative assessment of the lung cancer risk associated with occupational exposure to refractory ceramic fibers (RCF). The primary sources of data for our risk assessment were two long-term oncogenicity studies in male Fischer rats conducted to assess the potential pathogenic effects associated with prolonged inhalation of RCF. An interesting feature of the data was the availability of the temporal profile of fiber burden in the lungs of experimental animals. Because of this information, we were able to conduct both exposure-response and dose-response analyses. Our risk assessment was conducted within the framework of a biologically based model for carcinogenesis, the two-stage clonal expansion model, which allows for the explicit incorporation of the concepts of initiation and promotion in the analyses. We found that a model positing that RCF was an initiator had the highest likelihood. We proposed an approach based on biological considerations for the extrapolation of risk to humans. This approach requires estimation of human lung burdens for specific exposure scenarios, which we did by using an extension of a model due to Yu. Our approach acknowledges that the risk associated with exposure to RCF depends on exposure to other lung carcinogens. We present estimates of risk in two populations: (1) a population of nonsmokers and (2) an occupational cohort of steelworkers not exposed to coke oven emissions, a mixed population that includes both smokers and nonsmokers.

Administration, Inhalation↗
PubMed1999

Biologically based analysis of the data for the Colorado uranium miners cohort: age, dose and dose-rate effects.

This study is a comprehensive analysis of the latest follow-up of the Colorado uranium miners cohort using the two-stage clonal expansion model with particular emphasis on effects related to age and exposure. The model provides a framework in which the hazard function for lung cancer mortality incorporates detailed information on exposure to radon and radon progeny from hard rock and uranium mining together with information on cigarette smoking. Even though the effect of smoking on lung cancer risk is explicitly modeled, a significant birth cohort effect is found which shows a linear increase in the baseline lung cancer risk with birth year of the miners in the cohort. The analysis based on the two-stage clonal expansion model suggests that exposure to radon affects both the rate of initiation of intermediate cells in the pathway to cancer and the rate of proliferation of intermediate cells. However, in contrast to the promotional effect of radon, which is highly significant, the effect of radon on the rate of initiation is found to be not significant. The model is also used to study the inverse dose-rate effect. This effect is evident for radon exposures typical for mines but is predicted to be attenuated, and for longer exposures even reversed, for the more protracted and lower radon exposures in homes. The model also predicts the drop in risk with time after exposure ceases. For residential exposures, lung cancer risks are compared with the estimates from the BEIR VI report. While the risk estimates are in agreement with those derived from residential studies, they are about two- to fourfold lower than those reported in the BEIR VI report.

Age Factors↗
PubMed1998

Estimation of unit risk for coke oven emissions.

In 1984, based on epidemiological data on cohorts of coke oven workers, USEPA estimated a unit risk for lung cancer associated with continuous exposure from birth to 1 microgram/m3 of coke oven emissions, of 6.2 x 10(-4). This risk assessment was based on information on the cohorts available through 1966. Follow-up of these cohorts has now been extended to 1982 and, moreover, individual job histories, which were not available in 1984, have been constructed. In this study, lung cancer mortality in these cohorts of coke oven workers with extended follow-up was analyzed using standard techniques of survival analysis and a new approach based on the two stage clonal expansion model of carcinogenesis. The latter approach allows the explicit consideration of detailed patterns of exposure of each individual in the cohort. The analyses used the extended follow-up data through 1982 and the detailed job histories now available. Based on these analyses, the best estimate of unit risk is 1.5 x 10(-4) with 95% confidence interval = 1.2 x 10(-4)-1.8 x 10(-4).

Aged↗
PubMed1997

Air pollution and hospital admissions for respiratory causes in Minneapolis-St. Paul and Birmingham.

We investigated the association between air pollution and hospital admissions for chronic obstructive pulmonary disease and pneumonia among the elderly in Minneapolis-St. Paul, MN, and Birmingham, AL, over the period January 1, 1986, to December 31, 1991. Pollutants included in our analyses were PM10 (particulate matter less than 10 microns in aerodynamic diameter), SO2, NO2, O3, and CO in Minneapolis-St. Paul, and PM10, O3, and CO in Birmingham. After adjusting for temperature, day of week, season, and temporal trends, we found little evidence of association between air pollution and hospital admissions for respiratory causes in Birmingham. In contrast, we found that air pollution was associated with hospital admissions for respiratory causes in Minneapolis-St. Paul. Among the individual pollutants, O3 was most strongly associated with admissions (estimated increase in hospital admissions associated with a 15-parts-per-billion increase in O3 on the previous day = 5.15%; 95% confidence interval = 2.36-7.94%), and this association was robust in the sense that it was little affected by the simultaneous consideration of other pollutants. PM10, SO2, and NO2 were also associated with hospital admissions, although none could be singled out as being more important than the others.

Aged↗
PubMed1997

Some properties of the hazard function of the two-mutation clonal expansion model.

We discuss the hazard function of the two-mutation clonal expansion model with time-dependent parameters, with particular emphasis on identifiability of the parameters. We explicitly construct identifiable parameter combinations, and illustrate the properties of the hazard function under perturbations of the underlying biological parameters.

Animals↗
PubMed1997

Analysis of the incidence of solid cancer among atomic bomb survivors using a two-stage model of carcinogenesis.

A two-stage stochastic model for carcinogenesis was used to analyze the incidence of cancer of the lung, stomach and colon in the cohort of atomic bomb survivors. We fitted the model assuming that acute exposure to radiation results in the creation of initiated cells that are added to the pool of spontaneously initiated cells. In the cancers analyzed, with the exception of lung cancer in females, we found no evidence that radiation-induced initiation was dependent upon age at exposure. In contrast, we found that spontaneous initiation was dependent upon age at exposure in the cancers analyzed except stomach cancer among males. Because exposure to radiation in this cohort occurred at the same time for all members of the cohort, age at exposure is exactly 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 a dependence of radiation-induced initiation on age at exposure, 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 excess relative risk in this group is not due to an inherently higher sensitivity to radiation. Our biologically based approach provides another perspective on the temporal behavior of risk after acute exposure to ionizing radiation.

Adolescent↗
PubMed1996

A biologically based model for the analysis of premalignant foci of arbitrary shape.

In many animal carcinogenesis experiments, quantitative data on putative premalignant foci are now routinely collected. Moolgavkar et al. [Carcinogenesis 11:1271 (1990)] considered the analysis of such data from a rat hepatocarcinogenesis experiment within the framework of a two-stage model for carcinogenesis using the assumption that the premalignant clones were spherical. This assumption seems questionable in many organs, including the liver. In this paper, it is relaxed and arbitrary shapes are allowed for the clones. The proposed method is illustrated by reanalysis of the data considered in the earlier paper. The new analysis yields parameter estimates that are more plausible biologically than those of the original analysis.

Animals↗
PubMed1996

Quantitative analysis of enzyme-altered liver foci in rats initiated with diethylnitrosamine and promoted with 2,3,7,8-tetrachlorodibenzo-p-dioxin or 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin.

A quantitative method based upon a stochastic model was 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 from 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.

Adenosine Triphosphatases↗
PubMed1996

A critical review of the evidence on particulate air pollution and mortality.

We review epidemiologic studies of particulate air pollution and mortality in U.S. cities with respect to important methodologic issues. Many of these studies suffer from serious deficiencies in their control of the confounding effects of other pollutants. As a consequence, the small risks reported to be associated with the particulate component of air pollution could easily be attributed to residual confounding by co-pollutants. Most studies, moreover, have not considered modification of air pollution effects by seasonal factors, making the interpretation of the estimated risks difficult. We use a new analysis of mortality in Philadelphia that considers four pollutants simultaneously as well as seasonal effects to illustrate the methodologic issues raised in this paper. Air pollution, which is a complex mixture, appears to be associated with mortality even at the generally low levels of pollution in U.S. cities, but currently neither the statistical tools nor the biological understanding of mechanisms exists to tease out the contribution made by each component of this mixture. We conclude that it is not possible with the present evidence to show a convincing correlation between particulate air pollution and mortality.

Air Pollutants↗
PubMed1996

A biologically-based dose-response model for developmental toxicology.

The methods currently used to evaluate the risk of developmental defects in humans from exposure to potential toxic agents do not reflect biological processes in extrapolating estimated risks to low doses and from test species to humans. We develop a mathematical model to describe aspects of the dynamic process of organogenesis, based on branching process models of cell kinetics. The biological information that can be incorporated into the model includes timing and rates of dynamic cell processes such as differentiation, migration, growth, and replication. The dose-response models produced can explain patterns of malformation rates as a function of both dose and time of exposure, resulting in improvements in risk assessment and understanding of the underlying mechanistic processes. To illustrate the use of the model, we apply it to the prediction of the effects of methylmercury on brain development in rats.

Abnormalities, Drug-Induced↗
PubMed1996

Two-stage model of radon-induced malignant lung tumors in rats: effects of cell killing.

A two-stage stochastic model of carcinogenesis is used to analyze lung tumor incidence in 3750 rats exposed to varying regimens of radon carried on a constant-concentration uranium ore dust aerosol. New to this analysis is the parameterization of the model such that cell killing by the alpha particles could be included. The model contains parameters characterizing the rate of the first mutation, the net proliferation rate of initiated cells, the ratio of the rates of cell loss (cell killing plus differentiation) and cell division, and the lag time between the appearance of the first malignant cell and the tumor. Data analysis was by standard maximum likelihood estimation techniques. Results indicate that the rate of the first mutation is dependent on radon and consistent with in vitro rates measured experimentally, and that the rate of the second mutation is not dependent on radon. An initial sharp rise in the net proliferation rate of initiated cell was found with increasing exposure rate (denoted model I), which leads to an unrealistically high cell-killing coefficient. A second model (model II) was studied, in which the initial rise was attributed to promotion via a step function, implying that it is due not to radon but to the uranium ore dust. This model resulted in values for the cell-killing coefficient consistent with those found for in vitro cells. An "inverse dose-rate" effect is seen, i.e. an increase in the lifetime probability of tumor with a decrease in exposure rate. This is attributed in large part to promotion of intermediate lesions. Since model II is preferable on biological grounds (it yields a plausible cell-killing coefficient), such as uranium ore dust. This analysis presents evidence that a two-stage model describes the data adequately and generates hypotheses regarding the mechanism of radon-induced carcinogenesis.

Animals↗
PubMed1995

Incorporating cell proliferation kinetics into models for cancer risk assessment.

Some general principles in incorporating cell proliferation kinetics into dose-response models for cancer risk assessment are discussed. Two examples are presented in which a biologically-based dose-response model explicitly incorporating cell proliferation kinetics was used for the analysis of toxicologic data. In the first example, analysis of an initiation-promotion experiment in the rat liver, with diethylnitrosamine (DEN) as initiator and with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HCDD) as promoters, is presented. The results of the analysis indicate that, in addition to its promoting activity, TCDD has weak initiating activity. In the second example, multiple doses of N-nitrosomorpholine (NNM) were administered to rats in their drinking water and quantitative information on ATPase deficient foci in the liver recorded at various times. Additionally, a separate group of animals, administered the same doses, was followed until death and the presence or absence of malignant liver tumors recorded. The parameters of the model were estimated by fitting the model to these data and the estimated parameters were used to construct a dose-response curve for the probability of malignant tumors. Few malignant tumors were observed at the lower doses; however, the information on ATPase deficient foci can be used in the model to extend the range of the dose-response curve below the doses at which malignant tumors are observed.

Animals↗
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

Growth kinetics of enzyme-altered liver foci in rats treated with phenobarbital or alpha-hexachlorocyclohexane.

A quantitative method based upon a stochastic model for the appearance of initiated cells and their clonal growth was used to estimate cell birth and death rates in enzyme-altered liver foci (EAF). gamma-Glutamyltranspeptidase (gamma-GT)-positive foci were initiated in livers of female SPF Wistar rats by a single application of N-nitrosomorpholine. Serial terminations during and after stop of promoter treatment with either phenobarbital (PB) or alpha-hexachlorocyclohexane (alpha-HCH) provided information on the growth and regression of the EAF. Simultaneous labeling index (LI) measurements were obtained via single injections with [3H]thymidine. No significant increases of the LI were observed with PB or alpha-HCH treatment. Since both agents are strong liver promoters we conclude that the growth of gamma-GT-positive foci is mainly due to a decrease in the rate of apoptosis. Indeed, our analysis supports this conclusion but determines that the abrogation of homeostatic control during promoter treatment is subtle. The ratio of cell death and cell birth rate is found to be decreased only slightly during promoter treatment and slightly increased after stop of promotion. For the mathematical analysis, two distinct focal growth scenarios were employed: (i) volume growth, i.e., all cells within individual foci cycle actively with the same rate, and (ii) surface growth where only cells on the surface of foci cycle actively while interior cells are resting. The model based upon scenario (ii) provides a better fit to the data and is more consistent with the experimental observations indicating heterogeneity of cell division rates within individual foci.

Animals↗
PubMed1995

Air pollution and daily mortality in Philadelphia.

Many recent analyses have reported associations between air pollution and mortality in U.S. cities. In this paper, we present the results of regression analyses of daily mortality in Philadelphia during the period 1973-1988. Pollution variables included in the analyses were total suspended particulates (TSP), sulfur dioxide, and ozone. We controlled for the effects of weather on mortality by analyzing mortality separately for each season and explicityly including quintiles of temperature in the regression models. In regression models that consider weather and pollution variables simultaneously, daily mortality is associated with hot days in summer [relative risk (RR) for highest quintile of temperature = 1.07; 95% confidence interval (CI) = 1.04-1.10], and with cold days in spring (RR for lowest quintile of temperature = 1.07; 95% CI = 1.04-1.10), fall (RR for lowest quintile of temperature = 1.05; 95% CI = 1.02-1.08), and winter (RR for lowest quintile of temperature = 1.04; 95% CI = 1.01-1.07). When all three pollution covariates and weather are considered simultaneously in the regression model, ozone is associated with mortality in summer (RR = 1.15; 95% CI = 1.07-1.24) and sulfur dioxide is associated with mortality in spring (RR = 1.19; 95% CI = 1.06-1.33), fall (RR = 1.14; 95% CI = 1.00-1.29), and winter (RR = 1.21; 95% CI = 1.09-1.35), where the relative risks are for incremental changes of 100 parts per billion in ozone and sulfur dioxide on the previous day.(ABSTRACT TRUNCATED AT 250 WORDS)

Air Pollutants↗