Genetic background and 227Thorium as risk factors in biologically based models for induction of bone cancer in mice.

We explore the potential for the biologically based two-stage clonal expansion model to make statements about the influence of genetic factors on the steps in the model. We find evidence that the different susceptibility of BALB/C and CBA/Ca mice to bone cancer after (227)Thorium injection may be mostly due to different promotional responses to radiation. In BALB/C × CBA/Ca back-crossed mice, we analyzed the specific contribution of two individual loci in the carcinogenic process. This analysis suggests that the two high- or low-risk alleles are acting on promotion or on the background parameters, but not on radiation-induced initiation. Taken together with the comparison of CBA/Ca and BALB/C mice, this hints at the possibility that the two loci are candidates for modifying radiation-induced promotion.

Lung cancer mortality in the European uranium miners cohorts analyzed with a biologically based model taking into account radon measurement error.

The biologically based two-stage clonal expansion (TSCE) model is used to analyze lung cancer mortality of European miners from the Czech Republic, France, and Germany. All three cohorts indicate a highly significant action of exposure to radon and its progeny on promotion. The action on initiation is not significant in the French cohort. An action on transformation was tested but not found significant. In a pooled analysis, the results based on the French and German datasets do not differ significantly in any of the used parameters. For the Czech dataset, only lag time and two parameters that determine the clonal expansion without exposure and with low exposure rates (promotion) are consistent with the other studies. For low exposure rates, the resulting relative risks are quite similar. Exposure estimates for each calendar year are used. A model for random errors in each of these yearly exposures is presented. Depending on the used technique of exposure estimate, Berkson and classical errors are used. The consequences for the model parameters are calculated and found to be mostly of minor importance, except that the large difference in the exposure-induced initiation between the studies is decreased substantially.

Promotion of initiated cells by radiation-induced cell inactivation.

Cells on the way to carcinogenesis can have a growth advantage relative to normal cells. It has been hypothesized that a radiation-induced growth advantage of these initiated cells might be induced by an increased cell replacement probability of initiated cells after inactivation of neighboring cells by radiation. Here Monte Carlo simulations extend this hypothesis for larger clones: The effective clonal expansion rate decreases with clone size. This effect is stronger for the two-dimensional than for the three-dimensional situation. The clones are irregular, far from a circular shape. An exposure-rate dependence of the effective clonal expansion rate could come in part from a minimal recovery time of the initiated cells for symmetric cell division.

Promoting action of radiation in the atomic bomb survivor carcinogenesis data?

The age-time patterns of risk in the atomic bomb survivor data on incidence of solid cancers suggest an action of low-LET radiation not only on the initiating event but also on promotion in a biologically motivated model that allows for both actions. The favored model indicates a decrease of radiation risks with age at exposure due to the initiating effect and with time since exposure due to the promoting effect. These result in a relative risk that depends mostly on attained age for ages at exposure above 20 years. According to the model, a dose of 100 mGy is inducing about the same number of initiating events that occur spontaneously in 1 year. Assuming that several mutations are needed to obtain intermediate cells with growth advantage does not improve the quality of fit. The estimated promoting effect could be explained if the number of intermediate cells increases by 80% at 1 Gy, e.g. due to stimulated cell repopulation.

Lung cancer risk in mice: analysis of fractionation effects and neutron RBE with a biologically motivated model.

Data from Argonne National Laboratory on lung cancer in 15,975 mice with acute and fractionated exposures to gamma rays and neutrons are analyzed with a biologically motivated model with two rate-limiting steps and clonal expansion. Fractionation effects and effects of radiation quality can be explained well by the estimated kinetic parameters. Both an initiating and a promoting action of neutrons and gamma rays are suggested. While for gamma rays the initiating event is described well with a linear dose-rate dependence, for neutrons a nonlinear term is needed, with less effectiveness at higher dose rates. For the initiating event, the neutron RBE compared to gamma rays is about 10 when the dose rate during each fraction is low. For higher dose rates this RBE decreases strongly. The estimated lifetime relative risk for radiation-induced lung cancers from 1 Gy of acute gamma-ray exposure at an age of 110 days is 1.27 for male mice and 1.53 for female mice. For doses less than 1 Gy, the effectiveness of fractionated exposure to gamma rays compared to acute exposure is between 0.4 and 0.7 in both sexes. For lifetime relative risk, the RBE from acute neutrons at low doses is estimated at about 10 relative to acute gamma-ray exposure. It decreases strongly with dose. For fractionated neutrons, it is lower, down to about 4 for male mice.

The two-stage clonal expansion model as an example of a biologically based model of radiation-induced cancer.

A model with two stages and clonal expansion (TSCE) is reviewed as a prototype for biologically based models of cancer development. Applications of the TSCE model to data sets for animals and humans for particle radiation (alpha particles) are presented. The results suggest that the radiation not only influences the initiating mutation, but may also act as a promoter. A possible mechanism for the promoting action is described. The consequences of these results for the shapes of the radiation dose-response curves at low doses and dose rates are discussed.

Radiation-induced cell inactivation can increase the cancer risk.

Radiation can inactivate cells that are replaced by dividing neighboring cells. If cells on the way to malignancy can fill the deficit faster than healthy cells, their number increases. A major part of the radon-induced lung cancers in the Colorado miners can be explained by a moderate increase in the replacement probability.

A biologically based model for liver cancer risk in the Swedish thorotrast patients.

Data on liver tumors among 416 Swedish patients who were exposed to Thorotrast between 1930 and 1950 were analyzed with the biologically based two-step clonal expansion (TSCE) model. For background data, the Swedish Cancer Register for the follow-up period 1958 to 1997 was used. Effects of radiation on the initiating mutation and on the clonal expansion rate explained the observed patterns well. The TSCE model permits the deduction of several kinetic parameters of the postulated tumorigenesis process. Dose rates of 5 mGy/year double the spontaneous initiation rate. The clonal expansion rate is doubled by 80 mGy/year, and for females it reaches a plateau at dose rates beyond 240 mGy/year. For males the plateau is not significant. The magnitude of the estimated promoting effect of radiation can be explained with a moderate increase in the cell replacement probability for the intermediate cells in the liver, which is strikingly similar to the situation in lung tumorigenesis.

Analysis of a historical cohort of Chinese tin miners with arsenic, radon, cigarette smoke, and pipe smoke exposures using the biologically based two-stage clonal expansion model.

Hazelton, W. D., Luebeck, E. G., Heidenreich, W. F. and Moolgavkar, S. H. Analysis of a Historical Cohort of Chinese Tin Miners with Arsenic, Radon, Cigarette Smoke, and Pipe Smoke Exposures Using the Biologically Based Two-Stage Clonal Expansion Model. Radiat. Res. 156, 78-94 (2001).The two-stage clonal expansion model is used to analyze lung cancer mortality in a cohort of Yunnan tin miners based on individual histories with multiple exposures to arsenic, radon, cigarette smoke, and pipe smoke. Advances in methodology include the use of nested dose-response models for the parameters of the two-stage clonal expansion model, calculation of attributable risks for all exposure combinations, use of both a fixed lag and a gamma distribution to represent the time between generation of the first malignant cell and death from lung cancer, and scaling of biological parameters allowed by parameter identifiability. The cohort consists of 12,011 males working for the Yunnan Tin Corporation, with complete exposure records, who were initially surveyed in 1976 and followed through 1988. Tobacco and arsenic dominate the attributable risk for lung cancer. Of 842 lung cancer deaths, 21.4% are attributable to tobacco alone, 19.7% to a combination of tobacco and arsenic, 15.8% to arsenic alone, 11% to a combination of arsenic and radon, 9.2% to a combination of tobacco and radon, 8.7% to combination of arsenic, tobacco and radon, 5.5% to radon alone, and 8.7% to background. The models indicate that arsenic, radon and tobacco increase cell division, death and malignant conversion of initiated cells, but with significant differences in net cell proliferation rates in response to the different exposures. Smoking a bamboo water pipe or a Chinese long-stem pipe appears to confer less risk than cigarette use, given equivalent tobacco consumption.

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.

Two-step model for the risk of fatal and incidental lung tumors in rats exposed to radon.

Data from 4276 rats with radon exposures up to 10,000 WLM at rates up to 1000 WL are analyzed with a two-step clonal expansion model. The age dependences of the hazard for the risks for fatal and for incidental tumors are very different. Therefore, two different parameterizations of the model are used in the two cases. In both cases radiation acts only on the initiating mutation and the clonal expansion, but not on the second mutation. Average exposure rates of 5 WL for fatal tumors and 0.5 WL for incidental tumors double the rate of spontaneous mutations. While the fatal tumors show a linear increase in the effective clonal expansion rate up to about 100 WL average exposure rate and a saturation at higher exposure rates, the incidental tumors follow a step-like behavior of this parameter. It is proposed that only the fatal lung tumors among the rats be used for generalizations to models for lung cancer in humans. The fitted model for fatal tumors shows an inverse dose-rate effect at average exposure rates above 20 WL. However, below 10 WL the lung cancer risk per unit exposure decreases with increasing duration of exposure. Between 10 and 20 WL, the difference in ERR/WLM between acute and protracted exposure is small.

Time trends of thyroid cancer incidence in Belarus after the Chernobyl accident.

The rates of childhood thyroid cancer incidence observed in Belarus during the period 1986 to 1995 are described as a function of time after exposure, age at exposure, and sex. Conclusions are drawn for the excess absolute risk function. After a minimum latent period of about 3 years after exposure, this risk function has a linear increase with time for at least 6 years. After correction for the dependence of average doses on age, the radiation-induced absolute thyroid risk in Gomel is about a factor of 3 higher for children up to age 10 at exposure compared to older ones; this may be due in part to different case-collection quality. In addition, in the group up to 10 years at exposure, the thyroid of girls is more sensitive to radiation by a factor of about 1.5 than the thyroid of boys on an absolute scale. Risk estimates from external exposure are consistent with risk estimates from Gomel assuming that the increase in excess cases reaches a plateau soon.

Dose timing in tumor radiotherapy: considerations of cell number stochasticity.

A typical tumor radiotherapy regimen using external beam X rays consists of doses on weekdays for 4-7 weeks. During the final weeks, the tumor may contain only a few cells capable of regenerating the tumor and may be growing exponentially between doses. Stochastic fluctuations of the cell number can influence the optimal time pattern of dose delivery. If the total dose is fixed, a deterministic model of exponential tumor growth, neglecting stochastic effects, predicts that the way the radiation dose is spread out in time does not affect the average number of tumor cells at the end. However, we here show, within the framework of a birth-death model, that when stochastics are taken into account, the earlier the dose is given (consistent with other constraints imposed by quite different considerations), the better. The proof uses a transformation that simplifies the characteristic equation of the partial differential equation governing the probability generating function for a birth-death process with time-dependent rates. The theorem that earlier is better holds for any statistical distribution of cell number from patient to patient at the start of the exponential growth phase and for virtually any cell-killing model. Numerical results indicate the stochastic effects, although not dominant, are not negligible.

Age- and sex-specific relative thyroid radiation exposure to 131I in Ukraine after the Chernobyl accident.

The age- and sex-dependence of the 131I induced count rates is determined for the measurements performed in Ukraine after the Chernobyl accident on the thyroids of over 60,000 persons. For this, the individual measurements are scaled in such a way that the mean values over age and sex on one side and the mean values over measurement series on the other side are normalized to one. The resulting distribution of all scaled measurements is roughly log-normal. Half of them lie within a factor 1.6 of the median. 131I induced count rates have a minimum at birth year 1986, about half the value of adults. The maximum count rates with about 30% above adults are reached for males around age 16 y. The count rates are up to about 40% (at age 14-17 y) higher for males than for females. The results are within statistical uncertainties independent of the geographical area and the urban or rural nature of the settlements. Starting from the relative count rates, the age- and sex-dependence is calculated for the thyroid activities 1 mo after the accident for the integrated activities and for the doses. The dose of young children is a factor of about 6.5 higher than that of adults. Uncertainties are estimated throughout.

Interpretation by modelling of observations in radon radiation carcinogenesis.

Biophysical models for radon-related induction of lung cancer are developed with the aim of reducing the uncertainties in current risk estimates at low doses by a better understanding of the relevant mechanisms. These models can make use of the full dosimetric information when extracting information on, say, age-at-exposure, protraction or fractionation effects. It is found that irradiation by radon and its progeny does act on the initiating event of carcinogenesis (e.g. mutation), but its dominating effect is via promoting the division of already initiated cells. Data show that the concept of a unit of exposure giving, in an additive way, a unit of lung cancer risk is too limited, while relatively simple mechanistic assumptions described in this article do yield an adequate description of observations. Exposures in epidemiological data sets are measured with error. For various error models it has been shown that likelihood-based techniques of correction work reliably; likewise for biologically based cancer models. When several parameters are allowed to be exposure dependent, for example, initiation and promotion, then their relative importance is influenced.

A jammed finger from basketball.

A benign enchondroma of the left fifth distal interphalangeal joint occurred in a 39 year old male. The differential diagnoses and outcomes are discussed.

A mechanistic model for medulloblastoma induction in mice.

Medulloblastomas in Patched heterozygous mice (Ptc1(+/-) mice) are induced with high probability by ionizing radiation applied in the immediate post-natal period. A mathematical model is described here that accommodates the dependence of the medulloblastoma incidence on dose, age at exposure and age. The model assumes that the first step in the development of the cancer is already present in all cells of the patched mouse due to germ-line inactivation of one allele of the patched tumor suppressor gene. The subsequent rate-limiting step is dependent linearly on dose at least up to 3 Gy. The observed strong decrease in carcinogenic effect of radiation between exposure on day 1 and day 10 is described by a physiological elimination of target cells during post-natal maturation of the brain. A single malignant cell develops into a tumor following a gamma-distribution with mean of about 160 days. The multiplicity of medulloblastomas is predicted.

Systems biological and mechanistic modelling of radiation-induced cancer.

This paper summarises the five presentations at the First International Workshop on Systems Radiation Biology that were concerned with mechanistic models for carcinogenesis. The mathematical description of various hypotheses about the carcinogenic process, and its comparison with available data is an example of systems biology. It promises better understanding of effects at the whole body level based on properties of cells and signalling mechanisms between them. Of these five presentations, three dealt with multistage carcinogenesis within the framework of stochastic multistage clonal expansion models, another presented a deterministic multistage model incorporating chromosomal aberrations and neoplastic transformation, and the last presented a model of DNA double-strand break repair pathways for second breast cancers following radiation therapy.

Interaction of smoking and radon in rats: a biologically based mechanistic model.

Data on rats exposed to cigarette smoke before or after exposure to radon are used to estimate smoke-dependent parameters of the biologically based two-stage clonal expansion model. The baseline parameters and the action of radon acting on initiation and promotion were fixed based on earlier work. Cigarette smoke acting on transformation and inducing a reduction of the radon dose to the target cells after a smoking period gives an acceptable description of the data.