Influence of radiation dose patterns on lung tumor incidence in dogs that inhaled beta emitters: a preliminary report

Different radiation dose patterns to the lung from inhaled beta-emitting radionuclides may influence the frequency and kind of biological effects. To determine the magnitude of this influence, groups of Beagle dogs were exposed to aerosols of 90Y, 91Y, 144Ce, or 90Sr in relatively insoluble particles and observed for their life spans. Different dose patterns were achieved by using these radionuclides having similar beta emissions and chemical form but having physical half-lives ranging from 2.6 days to 28 years. The range of initial lung burdens of radionuclides studied resulted in a range of biological effects from early deaths at the highest radiation doses to no discernible effects at the lowest doses. The effective half-lives of the four radionuclides in the lung ranged from 2.5 to 600 days. Within 1.5 years after exposure, some dogs died with radiation pneumonitis and pulmonary fibrosis. Between 1.5 and 10 years after exposure, 42 pulmonary carcinomas and 28 pulmonary sarcomas were observed in 163 dogs that died. Protracted irradiation of the lung from 90Sr or 144Ce resulted in a relatively high radiation dose and produced more total lung tumors but fewer lung tumors per rad than less protracted irradiation from 90Y or 91Y. At 10 years after inhalation exposure, the difference in risk per rad among the different dose patterns was a factor of 4 to 8, indicating that the different radiation dose patterns from inhaled beta emitters do influence lung tumor risk factors, at least at high (greater than 20,000 rad) doses to lung.     

A single low dose of Fe ions can cause long-term biological responses in NL20 human bronchial epithelial cells

Space radiation cancer risk may be a potential obstacle for long-duration spaceflight. Among all types of cancer space radiation may induce, lung cancer has been estimated to be the largest potential risk. Although previous animal study has shown that Fe ions, the most important contributor to the total dose equivalent of space radiation, induced a higher incidence of lung tumorigenesis per dose than X-rays, the underlying mechanisms at cellular level remained unclear. Therefore, in the present study, we investigated long-term biological changes in NL20 human bronchial epithelial cells after exposure to Fe ion or X-ray irradiation. We found that compared with sham control, the progeny of NL20 cells irradiated with 0.1 Gy of Fe ions showed slightly increased micronucleus formation, significantly decreased cell proliferation, disturbed cell cycle distribution, and obviously elevated intracellular ROS levels accompanied by reduced SOD1 and SOD2 expression, but the progeny of NL20 cells irradiated with 0.9 Gy of X-rays did not show any significant changes. More importantly, Fe ion exposure caused much greater soft-agar colony formation than X-rays did in the progeny of irradiated NL20 cells, clearly suggesting higher cell transformation potential of Fe ions compared with X-rays. These data may shed the light on the potential lung tumorigenesis risk from Fe ion exposure. In addition, ATM inhibition by Ku55933 reversed some of the changes in the progeny of Fe ion-irradiated cells but not others such as soft-agar colony formation, suggesting complex processes from DNA damage to carcinogenesis. These data indicate that even a single low dose of Fe ions can induce long-term biological responses such as cell transformation, etc., suggesting unignorable health risk from space radiation to astronauts.     

Mortality from solid cancers other than lung,liver, and bone in relation to external dose among plutonium and non-plutonium workers in the Mayak Worker Cohort

Exposure to ionizing radiation has well-documented long-term effects on cancer rates and other health outcomes in humans. While in vitro experimental studies had demonstrated that the nature of some radiation effects depend on both total dose of the radiation and the dose rate (i.e., the pattern of dose distribution over time), the question of whether or not the carcinogenic effect of radiation exposure depends on the dose rate remains unanswered. Another issue of interest concerns whether or not concomitant exposure to external gamma rays and inhaled plutonium aerosols has any effect on the external exposure effects. The analyses of the present paper focus on the risk of solid cancers at sites other than lung, liver, and bone in Mayak workers. Recent findings are reviewed indicating that there is no evidence of plutonium dose response for these cancers in the Mayak worker cohort. Then the evidence for differences in the external dose effects among workers with and without the potential for exposure to alpha particles from inhaled plutonium is examined. It is found that there is no evidence that exposure to plutonium aerosols significantly affects the risk associated with external exposure. While the Mayak external dose risk estimate of an excess relative risk of 0.16 per Gy is somewhat lower than an appropriately normalized risk estimate from the Life Span Study of Japanese atomic bomb survivors, the uncertainties in these estimates preclude concluding that the external dose excess relative risks of this group of solid cancers differ in the two cohorts.     

Induction of sperm head abnormalities by incorporated radionuclides: dependence on subcellular distribution, type of radiation, dose rate, and presence of radioprotectors

In contrast to the biological effects caused by exposure to external beams of radiation, the effects of tissue-incorporated radionuclides are highly dependent on the type of radiation emitted and on their distribution at the macroscopic, microscopic, and subcellular levels, which are in turn determined by the chemical nature of the radionuclides administered. Induction of abnormalities of sperm heads in mice is investigated in this work after the injection of a variety of radiochemicals including alpha emitters. When the initial slopes of the dose-response curves are used to compare the relative biological effectiveness (RBE) of different radiocompounds, the alpha particles emitted in the decay of 210Po are more effective than Auger electrons emitted by 125I incorporated in the DNA of the spermatogonial cells, and both emissions are more effective than X rays. It is also shown that the Auger emitters (125I, 111In) distributed in the cell nucleus are more efficient in producing abnormalities than the same radionuclides localized in the cytoplasm. These findings are consistent with our earlier observations, where spermatogonial cell survival is assayed as a function of the testicular absorbed dose. Further, chronic irradiation of testis with gamma rays from intratesticularly administered 7Be is about three times more effective in causing abnormalities than a single acute exposure to 120-kVp X rays. The resulting RBE values correlate well with our data on sperm head survival with the same radiocompounds. Finally, the radioprotector cysteamine, when administered in small, nontoxic amounts, significantly reduces the incidence of sperm abnormalities from alpha-particle radiation as well as emissions from 125I incorporated into DNA, the dose reduction factors being 10 and 14, respectively.     

The dose response relationship obtained at constant irradiation times for the induction of chromosome aberrations in human lymphocytes by cobalt-60 gamma rays

Summary The induction of unstable chromosome aberrations in human peripheral blood lymphocytes exposed in vitro to protracted doses of cobalt-60 radiation is presented. Four dose response curves have been produced using constant exposure times of 1, 3, 6, and 12 h. The data fit well to the linear quadratic model and the yield coefficients have been compared with those obtained for acute (< 10 min) exposure. The quadratic coefficient is dependent on irradiation time and decreases approximately as predicted by Lea and Catcheside'sG-function hypothesis. The possibility of a small proportion of much longer lived breaks is discussed. For purposes of biological dosimetry it is sufficient to assume a mean time of 2 h and a single exponential function for the repair of lesions when relating the effects of brief and protracted exposure.     

The effect of prolonged gamma irradiation at a decreasing dose rate on survivability and gene mutation induction in cultured Chinese hamster cells

Continuous gamma irradiation at decreasing dose rate was shown to be less effective than acute exposure with regard to the lethal effect and frequency of mutations of resistance to 6-thioguanine in cultured Chinese hamster cells. The cell population subjected to continuous irradiation was more radioresistant than the intact one. Lethal and genetic effects of continuous irradiation at decreasing dose rate were mainly determined by the contribution of the radiation dose received during the first 24 h of exposure.     

Rapid proteomic remodeling of cardiac tissue caused by total body ionizing radiation

Accidental nuclear scenarios lead to environmental contamination of unknown level. Immediate radiation‐induced biological responses that trigger processes leading to adverse health effects decades later are not well understood. A comprehensive proteomic analysis provides a promising means to identify and quantify the initial damage after radiation exposure. Early changes in the cardiac tissue of C57BL/6 mice exposed to total body irradiation were studied, using a dose relevant to both intentional and accidental exposure (3 Gy gamma ray). Heart tissue protein lysates were analyzed 5 and 24 h after the exposure using isotope‐coded protein labeling (ICPL) and 2‐dimensional difference‐in‐gel‐electrophoresis (2‐D DIGE) proteomics approaches. The differentially expressed proteins were identified by LC‐ESI‐MS‐MS. Both techniques showed similar functional groups of proteins to be involved in the initial injury. Pathway analyses indicated that total body irradiation immediately induced biological responses such as inflammation, antioxidative defense, and reorganization of structural proteins. Mitochondrial proteins represented the protein class most sensitive to ionizing radiation. The proteins involved in the initial damage processes map to several functional categories involving cardiotoxicity. This prompts us to propose that these early changes are indicative of the processes that lead to an increased risk of cardiovascular disease after radiation exposure.     

Comparison of neutron organ and effective dose coefficients for PIMAL stylized phantom in bent postures in standard irradiation geometries

Neutron dose coefficients for standard irradiation geometries have been reported in International Commission on Radiological Protection (ICRP) Publication 116 for the ICRP Publication 110 adult reference phantoms. In the present work, organ and effective dose coefficients have been calculated for a receptor in both upright and articulated (bent) postures representing more realistic working postures exposed to a mono-energetic neutron radiation field. This work builds upon prior work by Dewji and co-workers comparing upright and bent postures for exposure to mono-energetic photon fields. Simulations were conducted using the Oak Ridge National Laboratory’s articulated stylized adult phantom, “Phantom wIth Moving Arms and Legs” (PIMAL) software package, and the Monte Carlo N-Particle (MCNP) version 6.1.1 radiation transport code. Organ doses were compared for the upright and bent (45° and 90°) phantom postures for neutron energies ranging from 1 × 10^??9 to 20 MeV for the ICRP Publication 116 external exposure geometries—antero-posterior (AP), postero-anterior (PA), and left and right lateral (LLAT, RLAT). Using both male and female phantoms, effective dose coefficients were computed using ICRP Publication 103 methodology. The resulting coefficients for articulated phantoms were compared to those of the upright phantom. Computed organ and effective dose coefficients are discussed as a function of neutron energy, phantom posture, and source irradiation geometry. For example, it is shown here that for the AP and PA irradiation geometries, the differences in the organ coefficients between the upright and bent posture become more pronounced with increasing bending angle. In the AP geometry, the brain dose coefficients are expectedly higher in the bent postures than in the upright posture, while all other organs have lower dose coefficients, with the thyroid showing the greatest difference. Overall, the effective dose estimated for the upright phantom is more conservative than that for the articulated phantom, which may have ramifications in the estimation or reconstruction of radiation doses.     

The effect of chronic gamma irradiation in an exponentially decreasing dose rate on the nucleic acid content in the hematopoietic organs and blood of rats]

The effect of continuous gamma irradiation at exponentially decreased dose rates (from 562 mGy/h to 13 mGy/h with a total cumulative dose of 14.355 Gy delivered over a period of 10 days) on the nucleic acid content of rat hemopoietic tissues and blood was followed up. The radiation model used simulated a decrease in the radioactivity of a fission mixture in the contaminated environment resulting from a nuclear device accident. We have found that the dynamics of the changes seems to be similar to that observed after acute exposure, and the hemopoiesis recovery starts just at the time of irradiation. In evaluating the damage and recovery extent after accidental irradiation, we consider it expedient to complement the biological dosimetry with the indices studied work including the determination of DNA and RNA concentrations in blood of irradiated human beings.     

Radiation factors and their influence on induction of oxygen resistance

Shortly after gamma irradiation, flour beetles exhibited a decline in resistance to oxygen toxicity. Then, about 2 weeks after irradiation, the 50% lethal dose (LD50) exposure time in pure oxygen was much greater than that of nonirradiated beetles, and this enhanced resistance persisted for about 6 months. The magnitude of the enhancement was a function of dose, decreased with increasing age at irradiation, and was modified by radiation factors. Both dose protraction and dose fractionation reduced the development of oxygen resistance to approximately the same degree that it reduced acute radiation lethality. This suggests that both the initial sensitization and the later enhancement of resistance are correlated with the residual biological damage rather than with the physical dose or initial damage.     

Sensitization to radiation from an implanted 125I source by sustained intratumoral release of chemotherapeutic drugs

We have investigated tumor response to low-dose-rate irradiation from an implanted 125I source alone or in conjunction with intratumoral drug administration. The drug (cis-DDP or 5-FU) was incorporated homogeneously into the co-polymer CPP-SA, 20:80, and the polymer/drug rods were implanted in the RIF-1 fibrosarcomas growing subcutaneously in C3H mice. Twenty-four hours later, the tumor was implanted with an 125I seed. Tumor growth time was the end point in these experiments. For implanted 125I sources of different dose rates and implant times giving a range of total doses, a consistent dose-response relationship was shown between tumor growth time and total dose. In other experiments, 125I sources of different specific activities were implanted for periods of time adjusted so that the total dose to the tumor was always the same. When the 125I implant was combined with 5-FU, greater than additive responses were seen for both short (30 h) and long (96 h) 125I treatment times. In contrast, a short-duration (30 h) 125I implant combined with cis-DDP was the least effective treatment, giving a combined response that was no better than additive, whereas 96 h exposure to 125I combined with cis-DDP was the most effective combined treatment. It is conjectured that this inverse dose-rate effect seen when cis-DDP is combined with low-dose rate radiation is related to a cell cycle effect and/or to inhibition of repair of radiation damage by cis-DDP.     

Childhood thyroid cancer, radiation dose from Chernobyl, and dose uncertainties in Bryansk Oblast, Russia: a population-based case-control study

A population-based case-control study was conducted to estimate the radiation-related risk of thyroid cancer in persons who were exposed in childhood to (131)I from the Chernobyl accident of April 26, 1986 and to investigate the impact of uncertainties in individual dose estimates. Included were all 66 confirmed cases of primary thyroid cancer diagnosed from April 26, 1986 through September 1998 in residents of Bryansk Oblast, Russia, who were 0-19 years old at the time of the accident, along with two individually matched controls for each case. Thyroid radiation doses, estimated using a semi-empirical model based on environmental contamination data and individual characteristics, ranged from 0.00014 Gy to 2.73 Gy and had large uncertainties (median geometric standard deviation 2.2). The estimated excess relative risk (ERR) associated with radiation exposure, 48.7/Gy, was significantly greater than 0 (P = 0.00013) but had an extremely wide 95% confidence interval (4.8 to 1151/Gy). Adjusting for dose uncertainty nearly tripled the ERR to 138/Gy, although this was likely an overestimate due to limitations in the modeling of dose uncertainties. The radiation-related excess risk observed in this study is quite large, especially if the uncertainty of dose estimation is taken into account, but is not inconsistent with estimates previously reported for risk after (131)I exposure or acute irradiation from external sources.     

Determining the repair rate for radiation-induced chromatid deletions during the first 24 hours after irradiation

The number of chromatid plus isochromatid deletions present in the testes and bone marrow of the Chinese hamster was measured as a function of time following acute exposure to cobalt-60 gamma irradiation. The number of breaks remaining scorable at any time after irradiation exposure could be represented by a simple exponential equation (N = Noe-kt). The values of No and k, calculated after 100 roentgens of cobalt-60 gamma irradiation, were 1.15 breaks/cell and 0.16/hour, respectively, for the testes, and 0.53 break/cell and 0.14/hour, respectively, for the bone marrow. The average length of time that the breaks remain scorable, 1/k, was found to be 6.3 hours for the testes and 7.1 hours for the bone marrow. By suitable formulation, it was possible to predict the number of breaks present by using varied radiation exposure rates and times after exposure. This formulation could be used for both single and multiple radiation exposures.     

Responses of the beagle to protracted irradiation. I. Effect of total dose and dose rate

The effects of protracted exposure to 60Co gamma rays on survival and tumor induction in the beagle were investigated. Total accumulated doses of 450, 1050, 1500, and 3000 cGy were given at rates of 3.8, 7.5, 12.8, and 26.3 cGy/day. Hazard models were used to identify trends in mortality associated with radiation exposure. The probability of an acute death (related to hematopoietic aplasia) was positively associated with the total dose received and the rate at which the dose was delivered. Once an animal survived the initial hematopoietic effects of radiation exposure, the risk of death from causes other than cancer, while elevated, was far less responsive than the neoplastic end points. No relationship between tumor or chronic nontumor deaths and dose rate could be identified. However, survival curves for tumor mortality did separate into a pattern clearly dependent on the accumulated dose.     

Chromosomal instability and delayed apoptosis in long-term T-lymphocyte cultures irradiated with carbon ions and x rays

In this study, we examined genomic instability induced by 250 kV X rays and 100 MeV/nucleon carbon ions in long-term lymphocyte cultures from two healthy donors. Two biological end points, delayed apoptosis and chromosomal instability, were studied in descendants of cells irradiated with three different doses of the particular radiation up to 22 population doublings. The delayed apoptosis showed no clear dependence on radiation dose, culture time or radiation quality. A persistent significant increase in the rate of apoptosis up to 36 days after X irradiation was observed for a dose of 4 Gy in donor 1 only. For both donors and radiations, de novo aberration yields were significantly increased in comparison to control values up to day 36. For both radiations, chromosome-type aberrations were seen more frequently than chromatid-type aberrations in both donors up to 22 days postirradiation. In both donors, carbon ions were more effective than X rays with respect to the induction of chromosome instability. A dose of 0.25 Gy of carbon ions corresponding to 1.4 ion traversals per cell nucleus was effective in the induction of instability in our cell system.     

Emphasis of biological research for space radiation]

The paper summarized issues, current status and the recent topics in biological research of space radiation. Researches to estimate a risk associated with space radiation exposure during a long-term manned space flight, such as in the International Space Station, is emphasized because of the large uncertainty of biological effects and a complexity of the radiation environment in space. The Issues addressed are; 1) biological effects and end points in low dose radiation, 2) biological effects under low dose rate and long-term radiation exposure, 3) modification of biological responses to radiation under space environments, 4) various aspects of biological end points vs. cellular and molecular mechanisms, 5) estimation of human risk associated with radiation exposure in space flight, 6) regulations for radiation exposure limits for space workers. The paper also summarized and introduced recent progress in space related radiation researches with various biological systems.     

Quantitative proteomic analysis reveals induction of premature senescence in human umbilical vein endothelial cells exposed to chronic low‐dose rate gamma radiation

Chronic low‐dose ionizing radiation induces cardiovascular disease in human populations but the mechanism is largely unknown. We suggested that chronic radiation exposure may induce endothelial cell senescence that is associated with vascular damage in vivo. We investigated whether chronic radiation exposure is causing a change in the onset of senescence in endothelial cells in vitro. Indeed, when exposed to continuous low‐dose rate gamma radiation (4.1 mGy/h), primary human umbilical vein endothelial cells (HUVECs) initiated senescence much earlier than the nonirradiated control cells. We investigated the changes in the protein expression of HUVECs before and during the onset of radiation‐induced senescence. Cellular proteins were quantified using isotope‐coded protein label technology after 1, 3, and 6 weeks of radiation exposure. Several senescence‐related biological pathways were influenced by radiation, including cytoskeletal organization, cell–cell communication and adhesion, and inflammation. Immunoblot analysis showed an activation of the p53/p21 pathway corresponding to the progressing senescence. Our data suggest that chronic radiation‐induced DNA damage and oxidative stress result in induction of p53/p21 pathway that inhibits the replicative potential of HUVECs and leads to premature senescence. This study contributes to the understanding of the increased risk of cardiovascular diseases seen in populations exposed to chronic low‐dose irradiation.     

Radiation injury: some aspects of the oncogenic effects.

The late effects or irradiation stem from cell killing, mutation, and malignant transformation. Cancer is the major somatic late effect of exposure to low dose levels of radiation, and estimates of risk of cancer in man after irradiation are based entirely on human experience. The data for dose-response relationships for the induction of tumors by external irradiation in man have been obtained from a single exposure or a small number of exposures delivered at high dose rates. In contrast, exposure to environmental irradiation is mainly protracted over a long period of time and is delivered at a low dose rate. As yet no allowance has been made for the effect of protraction of the exposure time in estimating the risk of cancer, although an adjustment has been made in the case of estimates of genetic risk. Incidence of tumors has been the only parameter used for risk estimates, but latent period and degree of malignancy, which are probably both dose and dose-rate dependent, influence the nature of the risk from radiation. As the knowledge about the effects of low-level radiation has been accumulated and assimilated over the last 70 years, so has the concern for reasonable standards of safety. There are still problems in the estimation of radiation risks, but at least many of the relevant questions can now be framed. The problems of estimating risks for chemical carcinogens are clearly greater, but the experience gained from radiation studies should help in the design of the necessary experiments.     

Acute biological effects of simulating the whole-body radiation dose distribution from a solar particle event using a porcine model

In a solar particle event (SPE), an unshielded astronaut would receive proton radiation with an energy profile that produces a highly inhomogeneous dose distribution (skin receiving a greater dose than internal organs). The novel concept of using megavoltage electron-beam radiation to more accurately reproduce both the total dose and the dose distribution of SPE protons and make meaningful RBE comparisons between protons and conventional radiation has been described previously. Here, Yucatan minipigs were used to determine the effects of a superficial, SPE-like proton dose distribution using megavoltage electrons. In these experiments, dose-dependent increases in skin pigmentation, ulceration, keratinocyte necrosis and pigment incontinence were observed. Five of 18 animals (one each exposed to 7.5 Gy and 12.5 Gy radiation and three exposed to 25 Gy radiation) developed symptomatic, radiation-associated pneumonopathy approximately 90 days postirradiation. The three animals from the highest dose group showed evidence of mycoplasmal pneumonia along with radiation pneumonitis. Moreover, delayed-type hypersensitivity was found to be altered, suggesting that superficial irradiation of the skin with ionizing radiation might cause immune dysfunction or dysregulation. In conclusion, using total doses, patterns of dose distribution, and dose rates that are compatible with potential astronaut exposure to SPE radiation, animals experienced significant toxicities that were qualitatively different from toxicities previously reported in pigs for homogeneously delivered radiation at similar doses.     

Risk of second primary thyroid cancer after radiotherapy for a childhood cancer in a large cohort study: an update from the childhood cancer survivor study

Previous studies have indicated that thyroid cancer risk after a first childhood malignancy is curvilinear with radiation dose, increasing at low to moderate doses and decreasing at high doses. Understanding factors that modify the radiation dose response over the entire therapeutic dose range is challenging and requires large numbers of subjects. We quantified the long-term risk of thyroid cancer associated with radiation treatment among 12,547 5-year survivors of a childhood cancer (leukemia, Hodgkin lymphoma and non-Hodgkin lymphoma, central nervous system cancer, soft tissue sarcoma, kidney cancer, bone cancer, neuroblastoma) diagnosed between 1970 and 1986 in the Childhood Cancer Survivor Study using the most current cohort follow-up to 2005. There were 119 subsequent pathologically confirmed thyroid cancer cases, and individual radiation doses to the thyroid gland were estimated for the entire cohort. This cohort study builds on the previous case-control study in this population (69 thyroid cancer cases with follow-up to 2000) by allowing the evaluation of both relative and absolute risks. Poisson regression analyses were used to calculate standardized incidence ratios (SIR), excess relative risks (ERR) and excess absolute risks (EAR) of thyroid cancer associated with radiation dose. Other factors such as sex, type of first cancer, attained age, age at exposure to radiation, time since exposure to radiation, and chemotherapy (yes/no) were assessed for their effect on the linear and exponential quadratic terms describing the dose-response relationship. Similar to the previous analysis, thyroid cancer risk increased linearly with radiation dose up to approximately 20 Gy, where the relative risk peaked at 14.6-fold (95% CI, 6.8-31.5). At thyroid radiation doses >20 Gy, a downturn in the dose-response relationship was observed. The ERR model that best fit the data was linear-exponential quadratic. We found that age at exposure modified the ERR linear dose term (higher radiation risk with younger age) (P < 0.001) and that sex (higher radiation risk among females) (P = 0.008) and time since exposure (higher radiation risk with longer time) (P < 0.001) modified the EAR linear dose term. None of these factors modified the exponential quadratic (high dose) term. Sex, age at exposure and time since exposure were found to be significant modifiers of the radiation-related risk of thyroid cancer and as such are important factors to account for in clinical follow-up and thyroid cancer risk estimation among childhood cancer survivors.