The use of biologically based cancer risk models in radiation epidemiology

Biologically based risk projection models for radiation carcinogenesis seek to describe the fundamental biological processes involved in neoplastic transformation of somatic cells into malignant cancer cells. A validated biologically based model, whose parameters have a direct biological interpretation, can also be used to extrapolate cancer risks to different exposure conditions with some confidence. In this article biologically based models for radiation carcinogenesis, including the two-stage clonal expansion (TSCE) model and its extensions, are reviewed. The biological and mathematical bases for such models are described, and the implications of key model parameters for cancer risk assessment examined. Specific applications of versions of the TSCE model to important epidemiological datasets are discussed, including the Colorado uranium miners' cohort; a cohort of Chinese tin miners; the lifespan cohort of atomic bomb survivors in Hiroshima and Nagasaki; and a cohort of over 200,000 workers included in the National Dose Registry (NDR) of Canada.     

A new view of radiation-induced cancer

Biologically motivated mathematical models are important for understanding the mechanisms of radiation-induced carcinogenesis. Existing models fall into two categories: (1) short-term formalisms, which focus on the processes taking place during and shortly after irradiation (effects of dose, radiation quality, dose rate and fractionation), and (2) long-term formalisms, which track background cancer risks throughout the entire lifetime (effects of age at exposure and time since exposure) but make relatively simplistic assumptions about radiation effects. Grafting long-term mechanisms on to short-term models is badly needed for modelling radiogenic cancer. A combined formalism was developed and applied to cancer risk data in atomic bomb survivors and radiotherapy patients and to background cancer incidence. The data for nine cancer types were described adequately with a set of biologically meaningful parameters for each cancer. These results suggest that the combined short-long-term approach is a potentially promising method for predicting radiogenic cancer risks and interpreting the underlying biological mechanisms.     

Growth curve analysis of tumourigenesis using cellular level cancer model

It is known that carcinogenesis by low-dose radiation will start from DNA damage by ionising radiation. After the long time period, these very small effects will appear on a cellular scale by accumulation of various intracellular biological responses and finally grow to the tumour with clonal expansion of cancer cell. Thus, the biological radiation effects are phenomena with a very wide scale from DNA damage (10(-9) m, 10(-6) s) to the tumour (10(-3) m, 10(5) s); so the risk estimation of low-dose radiation is difficult to study by the experiments. To overcome these difficult situations at low-dose radiation effects' problems, it is good to study the process of carcinogenesis using a biologically based mathematical model. This study's cellular-scale mathematical model of tumourigenesis and some results of the statistical calculations about the tumour growth as presented in the work.     

Dosimetric characteristics of Li2B4O7:Cu,Ag,P solid TL detectors

A two-mutation carcinogenesis (TMC) model is used as a bridge between cellular radiation biological effects and the incidence of cancer. This model has been applied to several sets of experimental animal and epidemiological data. In this paper the advantage of the model and the implications for radiation risks at low doses are discussed with respect to the age and dose dependence of cancer incidence and the effect of age at exposure on radiation risk; the link between the radiation effect and background cancer incidence and the transfer of radiation risk across different population groups; the implications of acute and protracted radiation exposures for risks at low doses and the dose-effect relationship for radium induced bone cancer.     

The genetics of radiation-induced osteosarcoma

Individual genetic variation can influence susceptibility to the carcinogenic effects of many environmental carcinogens. In radiation-exposed populations those individuals with a greater genetically determined susceptibility would be at greater risk of developing cancer. To include this modification of risk into radiation protection schemes it is necessary to identify the genes responsible for determining individual sensitivity. Alpha-particle-induced osteosarcoma in the mouse has been adopted as a model of human radiation carcinogenesis, and genome-wide screens have been conducted for allelic imbalance and genetic linkage. These studies have revealed a series of genes involved in determining the sensitivity to radiogenic osteosarcoma formation.     

Lower radiation weighting factor for radon indicated in mechanistic modelling of human lung cancer

A two-mutation carcinogenesis (TMC) model was fitted to the age-dependent lung cancer incidence in a cohort of Dutch Hodgkin patients treated with radiotherapy. Employing the results of previous TMC analyses of lung cancer due to smoking (by British doctors) and due to exposure to radon (for Colorado miners) a model fit was obtained with an estimate for the low LET radiation effect at the cellular level. This allows risk calculations for lung cancer from low LET radiation. The excess absolute risks are in tune with the values reported in the literature, the excess relative risks differ among the exposed groups. Comparing the cellular radiation coefficients for radon and for low LET radiation leads to an estimated radiation weighting factor for radon of 3 (0.1-6).     

Possible implications of non-linear radiobiological effects for the estimation of radiation risk at low doses

Possible implications of the effects of low LET radiation on the induction of cancer at low doses are studied. Low dose hypersensitivity and adaptive response were identified as candidates which may give a non-linear dose effect curve for acute exposures, whereas adaptive response may influence protracted exposures. In this paper acute exposures are studied. Several radiobiological reports on studies with mammalian cell lines have indicated the presence of a hypersensitive region in the radiation survival response at low doses followed by an increase in radioresistance. The two step clonal expansion (TSCE) model for the process of carcinogenesis was adapted in such a way that cell killing after acute radiation induces increased clonal expansion for some time and thus gives a promoting effect of radiation. As a first step, the Radiation Effects Research Foundation (RERF) data on the lung cancer incidence are fitted to study how such a model would influence the assessment of the cancer risk at low doses.     

A review of some epidemiological studies on cancer risk from low-dose radiation or other carcinogenic agents

It is extremely difficult to assess cancer risks accurately due to health effects of low-dose radiation exposure or other carcinogens based on epidemiological studies. For the detection of minute increases of the risk at low-level exposure, most of epidemiological studies lack statistical power, and they involve various complicated confounding factors. This paper reports on a literature survey of epidemiological studies published since 2000 on cancer risks associated with low-dose radiation and other carcinogens to gather major epidemiological data. Integrated risk indices were derived from those data by using, where possible, statistical models. Regarding risk assessment of low-dose radiation exposure, it is important to lower the degree of uncertainty arising from risk estimation. Risk assessment of low-dose radiation exposure could be scientific evidence when uncertainty is considered in comparing carcinogenic risks of radiation with those of other carcinogens.     

Radiation Effects on the Thermodiffusive Instability of Premixed Flames on a Cylindrical Porous Flame Holder

A linear analysis method was used to investigate the mechanics of radiation heat loss and mass transfer in the porous wall of premixed annular flames and their effect on thermodiffusive instability. The dispersion relation between the disturbance wave growth rate and wavenumber was calculated numerically. Results showed that radiation heat loss elevated the annular flame slightly away from the porous wall. In the annular flame with small Lewis numbers, radiation heat loss changed the thermodiffusive instability from a pulsating to a cellular state, while for the large Lewis numbers, only the pulsating instability was represented. Increasing radiation heat loss and the radius of the porous wall enhanced the instability of the annular flames. Heat losses decreased with the continued increase in thickness of the porous wall and the decrease in porosity. Annular flames with long-wave mode along the angular direction were more unstable than the shortwave mode.     

Non-targeted effects of radiation: bystander responses in cell and tissue models

The standard paradigm for radiation effects in cellular systems has involved direct damage to DNA and in particular, DNA double strand breaks as the triggering lesions leading to mutation, cell death and transformation. Recently, however, a growing body of evidence has reported non-targeted effects, which are not a direct consequence of the initial lesions produced in cellular DNA. These have included bystander responses, genomic instability, gene induction, adaptive responses and low dose hypersensitivity. A common observation of these responses is that they dominate at low doses and saturate with increasing dose. Non-targeted effects may therefore have consequences for extrapolation of risk estimates to low doses if these are important in vivo. A range of experimental techniques is being used to study non-targeted responses, including microbeam approaches. Microbeams have considerable advantages in that they allow individual cells and subcellular targets to be selected within populations with precise low doses and, if required, exact dose rates. Recent advances also allow targeting of 3-D cell systems. The mechanisms underlying non-targeted responses appear to involve production of reactive oxygen species and direct cell-to-cell signalling via gap junctional intercellular communication although significant differences exist in different cell types. The triggering lesions for these responses remain unclear however. Some non-targeted responses may be inter-related, for example in the case of bystander responses and instability and may be part of a general stress response system in irradiated populations. Some non-targeted effects may also act as protective mechanisms; if they lead to the removal of potentially damaged cells from the population.     

Use of various microdosimetric models for the prediction of radon induced damage in human lungs

Exposure to radon and radon decay products in some residential areas and at workplaces constitutes one of the greatest risks from natural sources of ionising radiation. Recently, increasing attention has been paid to the precise estimations of this health risk by numerous models. The compartmental model published in ICRP Publication 66 (HRTM) has been used for calculating alpha activity concentration in human lung. Energy deposition in the tissue was calculated by the Bethe-Bloch equation. The aim of this study was to check the performance and to compare the reliability of the microdosimetric models. In this work different thicknesses of mucus in the cases of non-smokers and smokers has been considered. Transformed cells were considered as the radiation risk parameters. The radiation risk evaluation for different exposure levels was based on homogeneous and heterogeneous distributions of target cells. The results of application of these procedures were compared with the epidemiological study of Czechoslovakian uranium miners.     

Health Canada's approach to manage risks to populations at risk during a radiological emergency

The approach that Health Canada uses to manage risks to individuals and to populations who might be exposed to ionising radiation is based upon the risk management paradigm. The paradigm differs little between an emergency and a non-emergency situations. In both events, technical experts assess the risk by determining the exposure to the source of radiation. They usually calculate the radiation dose and then assess the potential for any health effects. The initial technical assessments often use scoping calculations. The calculations for children recognise that they are smaller and have different metabolic rates and different behaviour from adults. However, most rigorous quantitative models for dosimetry do not differentiate between children and adults. The risk assessments that were conducted to evaluate the contamination of Canadians who were in London during the Litvenenko poisoning are a good example to illustrate this general approach. The scoping risk assessment concluded that the risks to children and adults were low. No Canadian children were exposed to polonium during this event and, to date, there have been no radiation emergencies in Canada where children have been exposed to a significant source of radiation. Therefore, the comparisons between theory and practice are very limited and conclusions are drawn from international experience and other incidents or sources of radiation exposure such as radon and medical exposures.     

A review of the bystander effect and its implications for low-dose exposure

Current models for the interaction between ionising radiation and living cells or tissues are based on direct genetic damage produced by energy deposition in cellular DNA. An important observation which has questioned this basic assumption is the radiation-induced bystander response, in which cells which have not been directly targeted respond if their neighbours have been exposed. This response predominates at low doses of relevance to radiation risk analysis (<0.2 Gy) and therefore needs to be fully characterised. The development of microbeams, which allow individual cells within populations to be targeted with precise doses of radiation, has provided a useful tool for quantifying this response. The authors' studies have targeted individual human and mouse cells with counted protons and helium ions and monitored neighbouring cells for the production of bystander responses. Bystander responses have been measured after exposures as low as a single proton or helium ion delivered to an individual cell. An important aspect is that these responses saturate with increasing dose to the single target cell, thus the relative roles of direct and indirect (non-targeted) responses change with dose. Studies with multicellular, tissue-based models are providing evidence that bystander responses may have a complex phenotype involving multiple pathways and the overall response may be a balance between multiple signalling processes and responses to radiation exposure. Current models for radiation risk assume a linear non-threshold response and have generally been extrapolated from high-dose exposures. The involvement of competing processes at low doses may have important consequences for understanding the effects of low-dose exposure.     

Delayed effects of chronic low-dose high linear energy transfer (LET) radiation on mice in vivo

In the present work, the delayed effects of chronic high linear energy transfer (LET) radiation in polychromatic erythrocytes (PCEs) of mice bone marrow were investigated in vivo. Irradiation of the two-month-old SHK white mongrel random-bred male mice was performed in the radiation field behind the concrete shield of the accelerator of 70 GeV protons to accumulate doses of 0.005-0.16 Gy. The dependence of the biological response on dose, adaptive response (AR) and genomic instability (GI) in F(1) and F(2) generations from males irradiated with doses of 0.005 and 0.16 Gy and from males exposed to combined action of immunomodulator-bendazol hydrochloride (BH) and of 0.16 Gy irradiation, were examined using the micronucleus formation test. The data demonstrated that irradiation of mice with these doses lead to an increase in the level of cytogenetic damage and induces no AR. With analysis of the bone marrow radiosensitivity to 1.5 Gy of X rays and the capacity to AR it was found that the chronic high-LET irradiation of parents induced the GI at least two generations. The combined exposure to BH and the dose of 0.16 Gy induces no AR in F(0) generation but induces AR in F(1) and F(2) offspring.     

Absorptive Bistability of Carbon Monoxide Initiated by Resonance Radiation

Abstract

The kinetics of the absorption of resonance radiation in carbon monoxide is analysed. It is found that when the radiation acts on high-lying vibrational energy levels of the CO molecule, absorptive bistability may arise. If the radiation flux is lower than a certain critical value, the gas is essentially transparent to radiation and the degree of vibrational non-equilibrium of the system is small. When the radiation flux exceeds a different critical value, we have another type of stable state. This state is characterized by a strong vibrational non-equilibrium, the radiation being effectively absorbed by the gas. Within the interval between these two critical values there are both lower and higher stable states of the system which are separated by an unstable state. A jump-like transition from one stable state to another, so called ‘absorptive instability’ is possible at certain values of the radiation flux and vibrational energy stored in the system. The development of absorptive instability is analysed in both isothermal and non-isothermal cases. A short-term decrease in the translational temperature is revealed at the initial stage of radiation absorption. It is found that the development of absorptive instability in a gas contained in a closed resonator is limited by the process of stimulated radiation which leads to a dissipation of the vibrational energy of the system. The fraction of the absorbed energy spent on this relaxation channel may approach unity.     

Modelling of intercellular induction of apoptosis in oncogenic transformed cells and radiation effects on the phenomenon

The removal of transformed cells via induction of apoptosis through intercellular signalling by surrounding cells is supposed to represent an important control mechanism limiting carcinogenesis. Low doses of radiation influence the efficiency of this anti-carcinogenesis process, indicating possible beneficial effects of low doses of radiation mediated by intercellular communication ('non-targeted effects'). To quantitatively understand the signalling system involved and the effects of radiation and to assess the role of this phenomenon in radiation-induced carcinogenesis, multi-scale modelling studies have been started. The proposed kinetic model takes into account (i) triggering of the effector function in cells in the vicinity of transformed cells, (ii) intercellular signalling between effector and transformed cells and (iii) execution of apoptosis in attacked cells. The systems model without radiation perturbance is reviewed. First results accounting for radiation-induced modulations of the signalling schemes are presented.     

Protection of normal cells from irradiation bystander effects by silica-flufenamic acid nanoparticles

The development of a myriad of nanoparticles types has opened new possibilities for the diagnostics and treatment of many diseases, especially for cancer. However, most of the researches done so far do not focus on the protection of normal cells surrounding a tumor from irradiation bystander effects that might lead to cancer recurrence. Gap-junctions are known to be involved in this process, which leads to genomic instability of neighboring normal cells, and flufenamic acid (FFA) is included in a new group of gap-junction blockers recently discovered. The present work explores the use of mesoporous silica nanoparticles MCM-41 functionalized with 3-Aminopropyltriethoxysilane (APTES) for anchoring the flufenamic acid for its prolonged and controlled release and protection from radiation bystander effects. MCM-41 and functionalized samples were structurally and chemically characterized with multiple techniques. The biocompatibility of all samples was tested in a live/dead assay performed in cultured MRC-5 and HeLa cells. HeLa cells cultured were exposed to 50?Gy of gamma-rays and the media transferred to fibroblast cells cultured separately. Our results show that MCM-41 and functionalized samples have high biocompatibility with MCR-5 and HeLa cells, and most importantly, the FFA delivered by these NPs was able to halt apoptosis, one of main bystander effects.