Georg Luebeck

A Two-Mutation Model for Radon-Induced Lung Tumors in Rats

The recessive oncogenesis model, according to which inactivation of both alleles of specific genes leads to cancer, has received much recent attention. A mathematical formulation of a two-mutation model for carcinogenesis, which includes the recessive oncogenesis model as a special case, was fitted to data from a large experimental study in which rats exposed to radon daughters developed malignant lung tumors. The model described the data well. The results indicate that fractionation of exposure increased the lifetime probability of tumor. Examination of the parameters of the model suggests that the effect of fractionation can be explained by the relative effects of radon daughters on the mutation rates and on the kinetics of growth of initiated cells. The first mutation rate is very strongly dependent upon the rate of exposure to radon daughters, the second mutation rate much less so, suggesting that the nature of the two mutational events is different. The model makes predictions which are testable in future experiments.

Diesel Engine Exhaust and Lung Cancer Mortality: Time-Related Factors in Exposure and Risk

To develop a quantitative exposure-response relationship between concentrations and durations of inhaled diesel engine exhaust (DEE) and increases in lung cancer risks, we examined the role of temporal factors in modifying the estimated effects of exposure to DEE on lung cancer mortality and characterized risk by mine type in the Diesel Exhaust in Miners Study (DEMS) cohort, which followed 12,315 workers through December 1997. We analyzed the data using parametric functions based on concepts of multistage carcinogenesis to directly estimate the hazard functions associated with estimated exposure to a surrogate marker of DEE, respirable elemental carbon (REC). The REC-associated risk of lung cancer mortality in DEMS is driven by increased risk in only one of four mine types (limestone), with statistically significant heterogeneity by mine type and no significant exposure-response relationship after removal of the limestone mine workers. Temporal factors, such as duration of exposure, play an important role in determining the risk of lung cancer mortality following exposure to REC, and the relative risk declines after exposure to REC stops. There is evidence of effect modification of risk by attained age. The modifying impact of temporal factors and effect modification by age should be addressed in any quantitative risk assessment (QRA) of DEE. Until there is a better understanding of why the risk appears to be confined to a single mine type, data from DEMS cannot reliably be used for QRA.

Testing goodness of fit for stochastic models of carcinogenesis

This paper considers the utility of statistical goodness of fit testing in the context of mechanistic models of carcinogenesis. Two stochastic models of carcinogenesis were tested with several sets of experimental and epidemiological data using a formal goodness of fit test specially designed to accommodate censored observations: these were the two-stage model allowing for clonal expansion of initiated cells and its simpler version with gamma distributed promotion time. The results of this application, supplemented by visual examination of local likelihood kernel estimates of the hazard function and the corresponding model-based estimates, show that mechanistic models of carcinogenesis provide a good fit to the data in the majority of cases under study.

Two Mutation Model for Carcinogenesis: Relative Roles of Somatic Mutations and Cell Proliferation in Determining Risk

Two experimental data sets are analyzed within the framework of a two-event model for carcinogenesis. In the first, the number and size distribution of altered hepatic foci, which are thought to be premaligant lesions, are analyzed as functions of dose of an administered agent (N-Nitrosomorpholine, NNM). Definitions of initiation and promotion potencies are proposed. Results of the analysis indicate that NNM is a strong initiator and a weak promoter. In the second, the time to appearance and the probability of malignant lung tumors in rats exposed to radon are analyzed as functions of total exposure and rate of exposure. The results indicate that fractionation of exposure increases the lifetime probability of tumor, and that the efficiency of fractionation can be explained by the relative effects of radon daughters on the mutation rates and the kinetics of growth of initiated cells.

Air Pollution, Pollens, and Admissions for Chronic Respiratory Disease in King County, Washington

We analyzed the association between various indices of air pollution, pollens, and hospital admissions for chronic respiratory disease in King County, WA, over the period 1987–1995. Both air pollution and tree pollens were independently associated with hospital admissions. In single-pollutant models, among the gases, we found the strongest association between carbon monoxide and hospitalization. The association with sulfur dioxide was weaker, and there was no evidence of an association with ozone. We also found association of hospital admissions with PM10, and a suggestion of an association with an index of light scattering measured by nephelometry. In two-pollutant models, the effect of carbon monoxide remained stable, whereas the effect of particulate matter, measured either as PM10 or by nephelometry, was attenuated and became unstable. We examined also the association between air pollution, pollens, and hospital admissions in three broad age groups, 0–19 yr, 20–64 yr, and 65 yr and older. Although tree pollens were associated with hospital admissions in each of these age groups, the association between air pollution and hospital admissions was seen only in the youngest age group.

Diesel Engine Exhaust and Lung Cancer Mortality: Time-Related Factors in Exposure and Risk: Diesel Engine Exhaust and Lung Cancer Mortality

To develop a quantitative exposure-response relationship between concentrations and durations of inhaled diesel engine exhaust (DEE) and increases in lung cancer risks, we examined the role of temporal factors in modifying the estimated effects of exposure to DEE on lung cancer mortality and characterized risk by mine type in the Diesel Exhaust in Miners Study (DEMS) cohort, which followed 12,315 workers through December 1997. We analyzed the data using parametric functions based on concepts of multistage carcinogenesis to directly estimate the hazard functions associated with estimated exposure to a surrogate marker of DEE, respirable elemental carbon (REC). The REC-associated risk of lung cancer mortality in DEMS is driven by increased risk in only one of four mine types (limestone), with statistically significant heterogeneity by mine type and no significant exposure-response relationship after removal of the limestone mine workers. Temporal factors, such as duration of exposure, play an important role in determining the risk of lung cancer mortality following exposure to REC, and the relative risk declines after exposure to REC stops. There is evidence of effect modification of risk by attained age. The modifying impact of temporal factors and effect modification by age should be addressed in any quantitative risk assessment (QRA) of DEE. Until there is a better understanding of why the risk appears to be confined to a single mine type, data from DEMS cannot reliably be used for QRA.

Diesel Engine Exhaust and Lung Cancer Mortality

To develop a quantitative exposure-response relationship between concentrations and durations of inhaled diesel engine exhaust (DEE) and increases in lung cancer risks, we examined the role of temporal factors in modifying the estimated effects of exposure to DEE on lung cancer mortality and characterized risk by mine type in the Diesel Exhaust in Miners Study (DEMS) cohort, which followed 12,315 workers through December 1997. We analyzed the data using parametric functions based on concepts of multistage carcinogenesis to directly estimate the hazard functions associated with estimated exposure to a surrogate marker of DEE, respirable elemental carbon (REC). The REC-associated risk of lung cancer mortality in DEMS is driven by increased risk in only one of four mine types (limestone), with statistically significant heterogeneity by mine type and no significant exposure-response relationship after removal of the limestone mine workers. Temporal factors, such as duration of exposure, play an important role in determining the risk of lung cancer mortality following exposure to REC, and the relative risk declines after exposure to REC stops. There is evidence of effect modification of risk by attained age. The modifying impact of temporal factors and effect modification by age should be addressed in any quantitative risk assessment (QRA) of DEE. Until there is a better understanding of why the risk appears to be confined to a single mine type, data from DEMS cannot reliably be used for QRA.