Data from animal experiments show that the radiation-related risk of cancer decreases if the dose rate is reduced, even though the cumulative dose is unchanged (i.e., a dose-rate effect); however, the underlying mechanism is not well understood. To explore factors underlying the dose-rate effect observed in experimental rat mammary carcinogenesis, we developed a mathematical model that accounts for cellular dynamics during carcinogenesis, and then examined whether the model predicts cancer incidence. A mathematical model of multistage carcinogenesis involving radiation-induced cell death and mutagenesis was constructed using differential equations. The mutation rate was changed depending on the dose rate. The model also considered competition among cells with various mutation levels. The main parameters of the model were determined using previous experimental data. The parameters of the model were consistent with experimental observations. A dose-rate effect on carcinogenesis became apparent when the relationship between dose rate and mutation rate was linear quadratic or quadratic. The dose-rate effect became prominent when cells with more mutations preferentially compensated for the radiation-induced death of cells with fewer mutations. The phenomenon by which mutated cells gain a competitive advantage over normal cells is known as super-competition. Here, we identified super-competition as a novel mechanism underlying the dose-rate effects on carcinogenesis. The data also confirmed the relevance of the shape of the relationship between dose rate and the mutation rate. Thus, this study provides new evidence for the mechanism underlying the dose-rate effect, which is important for predicting the cancer-related risks of low-dose-rate irradiation.

Ionizing radiation exposure during perinatal development can produce various biological effects on the developing offspring. These effects are dependent on a number of factors, including total dose, dose rate and the developmental processes occurring at the time of irradiation. The present study conducted an analysis of historical radiobiological archived data involving ⁶⁰Co-gamma irradiation of beagle dogs at specific periods of prenatal or postnatal development. The original studies were performed at two sites where animals were exposed to a single, acute dose of 0.2 or 1.0 Gy at six different stages of perinatal development or with protracted exposures ranging from 0.004 to 0.35 Gy per day, over multiple days of gestation. A number of outcomes were investigated after perinatal irradiation including changes in sex ratio, survival probability, disease incidence and growth of animals, based on collected size and weight measurements of animals and different tissues. Protracted irradiations with doses up to 0.35 Gy per day did not significantly affect survival in animals when irradiated prenatally, although significant increases in the incidence of neoplasms and diseases related to the cardiovascular and urogenital system were observed at the time of death. Dogs irradiated at a dose rate of 0.10 Gy per day, with the irradiations continuing after birth and resulting in the accumulation of large total doses, were observed to have chronic radiation syndrome symptoms based on pathologies related to the hematopoietic system. Acute irradiation with 0.2 and 1.0 Gy resulted in changes of different body or tissue sizes measured in animals terminally, with changes detected after irradiation at all tested prenatal and postnatal time points, with the exception of irradiation at 365 days after birth. The present analysis provides new information regarding the biological effects of ionizing radiation during perinatal development in offspring in the unique mammalian study model of the beagle dog.

BBT-059 is a long-acting PEGylated interleukin-11 analog that has been shown to have hematopoiesis-promoting and anti-apoptotic attributes, and is being studied as a radiation countermeasure for the hematopoietic acute radiation syndrome (H-ARS). This potential countermeasure has been demonstrated to enhance survival in irradiated mice. To investigate the toxicity and safety profile of this agent, 14 nonhuman primates (NHPs, rhesus macaques) were administered two different doses of BBT-059 subcutaneously 24 h after 4 Gy total-body irradiation and were monitored for the next 60 days postirradiation. Blood samples were investigated for the pharmacokinetics and pharmacodynamics of this agent and its effects on complete blood counts, cytokines, vital signs, and metabolomics. No adverse health effects were observed in either treatment group. Radiation-induced metabolomic dysregulation was observed in both treatment groups, and BBT-059 afforded some short-term radiomitigation. A few pathways were commonly dysregulated by radiation exposure including steroid hormone biosynthesis pathways, fatty acid activation, and glycerophospholipid metabolism. Notably, radiation-induced dysregulation to the linoleate metabolism pathway was significantly mitigated by either dose of BBT-059. In brief, this study suggests that BBT-059 has a good safety profile in irradiated NHPs and that its development as a medical countermeasure for U.S. Food and Drug Administration approval for human use should be continued.

Variable relative biological effectiveness (RBE) of carbon radiotherapy may be calculated using several models, including the microdosimetric kinetic model (MKM), stochastic MKM (SMKM), repair-misrepair-fixation (RMF) model, and local effect model I (LEM), which have not been thoroughly compared. In this work, we compared how these four models handle carbon beam fragmentation, providing insight into where model differences arise. Monoenergetic and spread-out Bragg peak carbon beams incident on a water phantom were simulated using Monte Carlo. Using these beams, input parameters for each model (microdosimetric spectra, DNA double-strand break yield, kinetic energy spectra, physical dose fragment contributions) were calculated for each contributing carbon beam fragment (hydrogen, helium, lithium, beryllium, boron, secondary carbon, primary carbon, electrons, and other). Scored input parameters for each fragment were used to calculate linear (α) and quadratic (β) parameters according to each model, which were combined with reference α and β values and absorbed physical dose to calculate RBE. Contributions from secondary fragments were found to exceed 30% of the total physical dose. Using identical beam parameters, the four models produced not only different RBE values but also different RBE trends. In all models, RBE was highest for secondary carbon ions. Beyond secondary carbons, the RBE magnitude typically increased with the atomic number of the fragment, but RBE trends differed dramatically by model and beamline region (entrance, spread-out Bragg peak, and tail). Variations in fragment RBE were large enough to be apparent in biological dose predictions. This study demonstrated that fragmentation is a nonnegligible consideration in carbon radiotherapy. Our findings identified differences in RBE among specific fragments and the four models, contributing to variability in the total biological dose across models. Because these findings emphasize differences in how various models handle carbon beam fragments, greater care should be taken in characterization of secondary fragments in particle therapy.

The role of genetics in susceptibility to radiotherapy-induced toxicities is unclear. A strong impact of genetics should cause correlated toxicities in patients with metachronous double radiotherapy. We ascertained information about demographics, lifestyle, radiotherapy and early toxicities in irradiated tissues for a retrospective cohort of 98 patients from 2 hospitals who underwent two metachronous radiotherapeutic treatments (2000–2022) of different anatomical regions. European Organisation for Research and Treatment of Cancer/Radiation Therapy Oncology Group (EORTC/RTOG) toxicity scores per organ system were combined to a single mean score. We considered as genetic component the variation of toxicity not explained by radiation dose to the tumor, age at radiotherapy, sex, smoking status, and surgery. Variance components of toxicity were evaluated by ordinal logistic regression with random intercept. Common site combinations were breast/contralateral breast (N = 16), breast/ endometrium (N = 6), and cervix/breast (N = 5). Mean toxicity over exposed tissues was 0.70 (range, 0–3). Prescribed radiation dose was significantly associated with mean toxicity, with a 5% (95% CI 3–8) increase of the odds for a higher toxicity level per Gy. Sex, surgery, age and smoking were not. There was no genetic contribution to risk of toxicities after adjustment. Toxicity levels were not more similar within patients than between patients, suggesting a negligible impact of genotype on radiotherapy-related toxicities.

Although leukemia in the Japanese atomic bomb survivor data has long exhibited upward curvature, until recently this appeared not to be the case for solid cancer. It has been suggested that the recently observed upward curvature in the dose response for the Japanese atomic bomb survivor solid cancer mortality data may be accounted for by flattening of the dose response in the moderate dose range (0.3–0.7 Gy). To investigate this, the latest version available of the solid cancer mortality and incidence datasets (with follow-up over the years 1950–2003 and 1958–2009 respectively) for the Life Span Study cohort of atomic bomb survivors was used to assess possible departures from linearity in the moderate dose range. Linear-spline models were fitted, also up to 6th order polynomial models in dose (higher order polynomials tended not to converge). The organ dose used for all solid cancers was weighted dose to the colon. There are modest indications of departures from linearity for the mortality data, whether using polynomial or linear-spline models. Use of the Akaike information criterion (AIC) suggests that the optimal model for the mortality data is given by a 5th order polynomial in dose. There is borderline significant (P = 0.071) indication of improvement provided by a linear-spline model in the mortality data. The low-dose extrapolation factor (LDEF), which measures the degree of overestimation of low-dose linear slope by the linear slope fitted over some specified dose range, is generally between 1.1–2.0 depending on the dose range, with upper confidence limits that sometimes exceed 10; although LDEF < 1 for the lowest dose range (<0.5 Gy), there are substantial uncertainties, with an upper confidence limit that exceeds 1.6. There are generally only modest indications of departures from linearity for the solid cancer incidence data, whether using polynomial or linear-spline models. In contrast to the mortality data, there are much weaker indications of improvement in fit provided by higher order polynomials, and only weak indications (P > 0.2) of improvement provided by linear-spline models. Nevertheless, use of AIC suggests that the optimal model for the incidence data is given by a 3rd order polynomial. LDEF evaluated over various dose ranges is generally between 1.2–1.4 with upper confidence limits that generally exceed 1.6; although LDEF < 1 for the lowest dose range (<0.5 Gy), there are substantial uncertainties, with an upper confidence limit that substantially exceeds 2.0. In summary, the evidence we have presented for higher order powers than the second in the dose response is not overwhelmingly strong, and is to some extent dependent on dose range. A feature of the dose response, which is reflected in the higher-order polynomials fitted to the data, is a leveling off or even a downturn in the response at doses >2 Gy. The linear-quadratic model is very widely used for modeling of dose response, and has been widely used in radiotherapy oncology applications as part of treatment planning. There is a theoretical basis for this model, based on the two-target model, although the data used to validate this has been mainly in vitro; there may be more complicated interactions than are implied by a two-target model, but the contributions made by these, which would contribute to higher order (than quadratic) powers of dose, may not be very pronounced over moderate ranges of dose.