Hyper-radiosensitivity affects low-dose acute myeloid leukemia incidence in a mathematical model.

In vitro experiments show that the cells possibly responsible for radiation-induced acute myeloid leukemia (rAML) exhibit low-dose hyper-radiosensitivity (HRS). In these cells, HRS is responsible for excess cell killing at low doses. Besides the endpoint of cell killing, HRS has also been shown to stimulate the low-dose formation of chromosomal aberrations such as deletions. Although HRS has been investigated extensively, little is known about the possible effect of HRS on low-dose cancer risk. In CBA mice, rAML can largely be explained in terms of a radiation-induced Sfpi1 deletion and a point mutation in the remaining Sfpi1 gene copy. The aim of this paper is to present and quantify possible mechanisms through which HRS may influence low-dose rAML incidence in CBA mice. To accomplish this, a mechanistic rAML CBA mouse model was developed to study HRS-dependent AML onset after low-dose photon irradiation. The rAML incidence was computed under the assumptions that target cells: (1) do not exhibit HRS; (2) HRS only stimulates cell killing; or (3) HRS stimulates cell killing and the formation of the Sfpi1 deletion. In absence of HRS (control), the rAML dose-response curve can be approximated with a linear-quadratic function of the absorbed dose. Compared to the control, the assumption that HRS stimulates cell killing lowered the rAML incidence, whereas increased incidence was observed at low doses if HRS additionally stimulates the induction of the Sfpi1 deletion. In conclusion, cellular HRS affects the number of surviving pre-leukemic cells with an Sfpi1 deletion which, depending on the HRS assumption, directly translates to a lower/higher probability of developing rAML. Low-dose HRS may affect cancer risk in general by altering the probability that certain mutations occur/persist.

Modeling low-dose radiation-induced acute myeloid leukemia in male CBA/H mice.

The effect of low-dose ionizing radiation exposure on leukemia incidence remains poorly understood. Possible dose-response curves for various forms of leukemia are largely based on cohorts of atomic bomb survivors. Animal studies can contribute to an improved understanding of radiation-induced acute myeloid leukemia (rAML) in humans. In male CBA/H mice, incidence of rAML can be described by a two-hit model involving a radiation-induced deletion with Sfpi1 gene copy loss and a point mutation in the remaining Sfpi1 allele. In the present study (historical) mouse data were used and these processes were translated into a mathematical model to study photon-induced low-dose AML incidence in male CBA/H mice following acute exposure. Numerical model solutions for low-dose rAML incidence and diagnosis times could respectively be approximated with a model linear-quadratic in radiation dose and a normal cumulative distribution function. Interestingly, the low-dose incidence was found to be proportional to the modeled number of cells carrying the Sfpi1 deletion present per mouse following exposure. After making only model-derived high-dose rAML estimates available to extrapolate from, the linear-quadratic model could be used to approximate low-dose rAML incidence calculated with our mouse model. The accuracy in estimating low-dose rAML incidence when extrapolating from a linear model using a low-dose effectiveness factor was found to depend on whether a data transformation was used in the curve fitting procedure.

How radiation influences atherosclerotic plaque development: a biophysical approach in ApoE⁻/⁻ mice.

Atherosclerosis is the development of lipid-laden plaques in arteries and is nowadays considered as an inflammatory disease. It has been shown that high doses of ionizing radiation, as used in radiotherapy, can increase the risk of development or progression of atherosclerosis. To elucidate the effects of radiation on atherosclerosis, we propose a mathematical model to describe radiation-promoted plaque development. This model distinguishes itself from other models by combining plaque initiation and plaque growth, and by incorporating information from biological experiments. It is based on two consecutive processes: a probabilistic dose-dependent plaque initiation process, followed by deterministic plaque growth. As a proof of principle, experimental plaque size data from carotid arteries from irradiated ApoE[Formula: see text] mice was used to illustrate how this model can provide insight into the underlying biological processes. This analysis supports the promoting role for radiation in plaque initiation, but the model can easily be extended to include dose-related effects on plaque growth if available experimental data would point in that direction. Moreover, the model could assist in designing future biological experiments on this research topic. Additional biological data such as plaque size data from chronically-irradiated mice or experimental data sets with a larger variety in biological parameters can help to further unravel the influence of radiation on plaque development. To the authors' knowledge, this is the first biophysical model that combines probabilistic and mechanistic modeling which uses experimental data to investigate the influence of radiation on plaque development.

Modeling Lung Carcinogenesis in Radon-Exposed Miner Cohorts: Accounting for Missing Information on Smoking.

Epidemiological miner cohort data used to estimate lung cancer risks related to occupational radon exposure often lack cohort-wide information on exposure to tobacco smoke, a potential confounder and important effect modifier. We have developed a method to project data on smoking habits from a case-control study onto an entire cohort by means of a Monte Carlo resampling technique. As a proof of principle, this method is tested on a subcohort of 35,084 former uranium miners employed at the WISMUT company (Germany), with 461 lung cancer deaths in the follow-up period 1955-1998. After applying the proposed imputation technique, a biologically-based carcinogenesis model is employed to analyze the cohort's lung cancer mortality data. A sensitivity analysis based on a set of 200 independent projections with subsequent model analyses yields narrow distributions of the free model parameters, indicating that parameter values are relatively stable and independent of individual projections. This technique thus offers a possibility to account for unknown smoking habits, enabling us to unravel risks related to radon, to smoking, and to the combination of both.

The ICRP, MELODI, and ALLIANCE workshop on effects of ionizing radiation exposure in offspring and next generations: a summary of discussions.

PURPOSE: Task Group 121 - Effects of ionizing radiation exposure in offspring and next generations - is a task group under the Committee 1 of the International Commission on Radiological Protection (ICRP), approved by the Main Commission on 18th November 2021. The main goals of Task Group 121 are to (1) review and update the scientific literature of relevance to radiation-related effects in the offspring of parent(s) exposed to ionizing radiation in both human and non-human biota; (2) to assess preconceptional and intrauterine effects of radiation exposure and related morbidity and mortality; and, (3) to provide advice about the level of evidence and how to consider these preconceptional and postconceptional effects in the system of radiological protection for humans and non-human biota. METHODS: The Task Group is reviewing relevant literature since Publication 90 'Biological effects after prenatal irradiation (embryo and fetus)' (2003) and will include radiation-related effects on future generations in humans, animals, and plants. This review will be conducted to account for the health effects on offspring and subsequent generations in the current system of radiological protection. Radiation detriment calculation will also be reviewed. Finally, preliminary recommendations will be made to update the integration of health effects in offspring and next generations in the system of radiological protection. RESULTS: A Workshop, jointly organized by ICRP Task Group 121 and European Radiation Protection Research Platforms MELODI and ALLIANCE was held in Budapest, Hungary, from 31st May to 2nd June 2022. Participants discussed four important topics: (1) hereditary and epigenetic effects due to exposure of the germ cell line (preconceptional exposure), (2) effects arising from exposure of the embryo and fetus (intrauterine exposure), (3) transgenerational effects on biota, and (4) its potential impact on the system of radiological protection. CONCLUSIONS: Based on the discussions and presentations during the breakout sessions, newer publications, and gaps on the current scientific literature were identified. For instance, there are some ongoing systematic reviews and radiation epidemiology reviews of intrauterine effects. There are newer methods of Monte Carlo simulation for fetal dosimetry, and advances in radiation genetics, epigenetics, and radiobiology studies. While the current impact of hereditary effects on the global detriment was reported as small, the questions surrounding the effects of radiation exposure on offspring and the next generation are crucial, recurring, and with a major focus on exposed populations. This article summarizes the workshop discussions, presentations, and conclusions of each topic and introduces the special issue of the International Journal of Radiation Biology resulting from the discussions of the meeting.

Support for the "Vancouver call for action to strengthen expertise in radiological protection worldwide": the position of organisations in formal relations with the International Commission on Radiological Protection (ICRP).

The International Commission on Radiological Protection (ICRP), recently expressed concern that "a shortage of investment in training, education, research, and infrastructure seen in many sectors and countries may compromise society's ability to properly manage radiation risks" and in 2022 announced the "Vancouver call for action to strengthen expertise in radiological protection worldwide". As representatives of organisations in formal relations with ICRP, we decided to promote this position paper to declare and emphasise that strengthening the expertise in radiological protection is a collective priority for all of us.

International expert group collaboration for developing an adverse outcome pathway for radiation induced leukemia.

PURPOSE: The concept of the adverse outcome pathway (AOP) has recently gained significant attention as to its potential for incorporation of mechanistic biological information into the assessment of adverse health outcomes following ionizing radiation (IR) exposure. This work is an account of the activities of an international expert group formed specifically to develop an AOP for IR-induced leukemia. Group discussions were held during dedicated sessions at the international AOP workshop jointly organized by the MELODI (Multidisciplinary European Low Dose Initiative) and the ALLIANCE (European Radioecology Alliance) associations to consolidate knowledge into a number of biological key events causally linked by key event relationships and connecting a molecular initiating event with the adverse outcome. Further knowledge review to generate a weight of evidence support for the Key Event Relationships (KERs) was undertaken using a systematic review approach. CONCLUSIONS: An AOP for IR-induced acute myeloid leukemia was proposed and submitted for review to the OECD-curated AOP-wiki (aopwiki.org). The systematic review identified over 500 studies that link IR, as a stressor, to leukemia, as an adverse outcome. Knowledge gap identification, although requiring a substantial effort via systematic review of literature, appears to be one of the major added values of the AOP concept. Further work, both within this leukemia AOP working group and other similar working groups, is warranted and is anticipated to produce highly demanded products for the radiation protection research community.

A two-mutation model of radiation-induced acute myeloid leukemia using historical mouse data.

From studies of the atomic bomb survivors, it is well known that ionizing radiation causes several forms of leukemia. However, since the specific mechanism behind this process remains largely unknown, it is difficult to extrapolate carcinogenic effects at acute high-dose exposures to risk estimates for the chronic low-dose exposures that are important for radiation protection purposes. Recently, it has become clear that the induction of acute myeloid leukemia (AML) in CBA/H mice takes place through two key steps, both involving the Sfpi1 gene. A similar mechanism may play a role in human radiation-induced AML. In the present paper, a two-mutation carcinogenesis model is applied to model AML in several data sets of X-ray- and neutron-exposed CBA/H mice. The models obtained provide good fits to the data. A comparison between the predictions for neutron-induced and X-ray-induced AML yields an RBE for neutrons of approximately 3. The model used is considered to be a first step toward a model for human radiation-induced AML, which could be used to estimate risks of exposure to low doses.

Bone cancer risk of (239)pu in humans derived from animal models.

Two-mutation model fits to bone cancer mortality data from mice, rats and beagle dogs injected with (239)Pu or (226)Ra show that (1) it is possible to fit the radiation-related parameters for animals from different strains of the same species together; (2) for every species the same significant parameters are found in the models for (239)Pu and in the models for (226)Ra, and the only difference is in the value of the linear mutation coefficient; and (3) the toxicity ratio, when defined as the ratio of the linear mutation coefficients for (239)Pu over (226)Ra, has a relatively uniform value of approximately 8 for the species considered. This relatively constant ratio enables the development of a (239)Pu model for humans that is based on the radium dial painters and the toxicity ratio for beagles. The model predictions agree well with published risk estimates based on other data and derived using alternative approaches. This has two important implications: (1) The two-mutation model appears to be a useful tool in translating from animal models to humans in a meaningful way; and (2) once a two-mutation model for humans has been derived, radiation risks can be calculated that depend on doses, dose rates and ages at exposure. Such a model therefore supplements published risk estimates that often lack such dependences.

Modelling breast cancer in a TB fluoroscopy cohort: implications for the Dutch mammography screening.

Breast cancer incidence in a tuberculosis fluoroscopy cohort has been modelled with a two-stage carcinogenesis model. The relatively simple model, in which hormonal influences only affect the number of sensitive target cells, fits the data very well. Under the assumption that individual hormonal differences average out, and with a relative biological effectiveness for mammographic X rays of 1, the model yields ∼10 fatal breast cancer cases induced by the entire Dutch screening programme over a period of 25 y. This is much lower than derived from standard ICRP risk estimates and should be compared with the number of lives saved, which is estimated at ∼350 y(-1). As the extent of screening is currently being reconsidered in The Netherlands and elsewhere, this is an important result.

Modelling lung cancer due to radon and smoking in WISMUT miners: preliminary results.

A mechanistic two-stage carcinogenesis model has been applied to model lung-cancer mortality in the largest uranium-miner cohort available. Models with and without smoking action both fit the data well. As smoking information is largely missing from the cohort data, a method has been devised to project this information from a case-control study onto the cohort. Model calculations using 256 projections show that the method works well. Preliminary results show that if an explicit smoking action is absent in the model, this is compensated by the values of the baseline parameters. This indicates that in earlier studies performed without smoking information, the results obtained for the radiation parameters are still valid. More importantly, the inclusion of smoking-related parameters shows that these mainly influence the later stages of lung-cancer development.

Lung cancer from radon: a two-stage model analysis of the WISMUT Cohort, 1955-1998.

A biologically based two-stage carcinogenesis model is applied to epidemiological data for lung cancer mortality in a large uranium miner cohort of the WISMUT company (Germany). To date, this is the largest uranium miner cohort analyzed by a mechanistic model, comprising 35,084 workers among whom 461 died from lung cancer in the follow-up period 1955-1998. It comprises only workers who were first employed between 1955 and 1989 and contains information on annual exposures to radon progeny. We fitted the model's free parameters, including the average growth time of one malignant cell into a lethal tumor. This lag time has an extraordinary value of 13 to 14 years, larger than that previously used or found in miner studies. Even though cohort-wide information on smoking habits is limited and the calendar-year dependence of tobacco smoke exposure was only implicitly accounted for by a birth cohort effect, we find good agreement between the modeled (expected) and empirical (observed) lung cancer mortality. Model calculations of excess relative lung cancer death risk agree well with those from the descriptive, BEIR VI-type exposure-age-concentration model for WISMUT miners. The large variety of exposure profiles in the cohort leads to a well-determined mechanistic model that in principle allows for an extrapolation from occupational to indoor radon exposure.

Breast cancer risk from different mammography screening practices.

Mammography screening is an accepted procedure for early detection of breast tumors among asymptomatic women. Since this procedure involves the use of X rays, it is itself potentially carcinogenic. Although there is general consensus about the benefit of screening for older women, screening practices differ between countries. In this paper radiation risks for these different practices are estimated using a new approach. We model breast cancer induction by ionizing radiation in a cohort of patients exposed to frequent X-ray examinations. The biologically based, mechanistic model provides a better foundation for the extrapolation of risks to different mammography screening practices than empirical models do. The model predicts that the excess relative risk (ERR) doubles when screening starts at age 40 instead of 50 and that a continuation of screening at ages 75 and higher carries little extra risk. The number of induced fatal breast cancers is estimated to be considerably lower than derived from epidemiological studies and from internationally accepted radiation protection risks. The present findings, if used in a risk-benefit analysis for mammography screening, would be more favorable to screening than estimates currently recommended for radiation protection. This has implications for the screening ages that are currently being reconsidered in several countries.