Chromosome aberrations in peripheral lymphocytes and radiation dose to active bone marrow in patients treated for cancer of the cervix

An international study of cervical cancer patients reported a doubling of the risk for leukemia following radiotherapy. To evaluate the extent of residual chromosome damage in circulating T-cell lymphocytes in this population, approximately 200 metaphases were examined from each of 96 irradiated and 26 nonirradiated cervical cancer patients treated more than 17 years ago (average 23 years). Radiation dose averaged over the total red bone marrow was estimated to be 8.1 Gy. The type and frequency of stable and unstable chromosome aberrations were quantified in 24,117 metaphases. Unstable aberrations did not differ significantly between irradiated and nonirradiated patients (P greater than 0.5). Stable aberrations (i.e., translocations, inversions, or chromosomes with deleted segments), however, were significantly higher among irradiated (2.8 per 100 cells) compared to nonirradiated (0.7 per 100 cells) women (P less than 10(4). The frequency of these stable aberrations was found to increase significantly with increasing dose to the bone marrow. These data indicate that a direct relationship between radiation dose and extent of damage to somatic cells persists in populations and can be detected many years after partial-body radiation exposure. The stable aberration rate in irradiated cervical cancer patients was 50 to 75% lower than those observed 25 years or more after radiation exposure in atomic bomb survivors and in ankylosing spondylitis patients treated with radiotherapy. The average marrow dose was only 1 Gy in the examined atomic bomb survivors and 3.5 Gy in the ankylosing spondylitis patients. It appears, then, that a very high dose delivered to the pelvic cavity in fractionated doses resulted in far fewer persistent stable aberrations than lower doses delivered either in acute whole-body exposure or in fractionated doses to the spinal column and sacroiliac joints. The higher radiation dose and the concentration of that dose in a smaller area of the body appear to be responsible for the lower rate of persistent aberrations observed in cervical cancer patients.     

Trends in childhood leukaemia in the Nordic countries in relation to fallout from atmospheric nuclear weapons testing.

OBJECTIVE--To obtain further information about the risks of childhood leukaemia after exposure to ionising radiation at low doses and low dose rates before or after birth or to the father''s testes shortly before conception. DESIGN--Observational study of trends in incidence of childhood leukaemia in relation to estimated radiation exposures due to fallout from atmospheric nuclear weapons testing during the 1950s and 1960s. SETTING--Nordic countries. SUBJECTS--Children aged under 15 years. MAIN OUTCOME MEASURES--Incidence rates of leukaemia by age at diagnosis, sex, country, and calendar year of diagnosis or year of birth; exposure category; relation between leukaemia and exposure for children aged 0-14 and 0-4 separately. RESULTS--During the high fallout period the average estimated dose equivalent to the fetal red bone marrow was around 140 mu Sv and the average annual testicular dose 140 mu Sv. There was little evidence of increased incidence of leukaemia among children born in these years. Doses to the red bone marrow of a child after birth were higher, and during the high exposure period children would have been subjected to an additional dose equivalent of around 1500 mu Sv, similar to doses received by children in several parts of central and eastern Europe owing to the Chernobyl accident and about 50% greater than the annual dose equivalent to the red bone marrow of a child from natural radiation. leukaemia incidence and red marrow dose was not related overall, but rates of leukaemia in the high exposure period were slightly higher than in the surrounding medium exposure period (relative risk for ages 0-14: 1.07, 95% confidence interval 1.00 to 1.14; for ages 0-4: 1.11, 1.00 to 1.24). CONCLUSIONS--Current predicted risks of childhood leukaemia after exposure to radiation are not greatly underestimated for low dose rate exposures.     

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.     

Influence of dose rate on survival time for 239PuO2-induced radiation pneumonitis or pulmonary fibrosis in dogs.

Beagle dogs were exposed once or repeatedly to 0.75-microns-diameter monodisperse aerosols of 239PuO2 by pernasal inhalation. The dogs that were exposed once received alveolar depositions (+/- standard deviation) of 3.9 +/- 1.9 kBq/kg body mass and accumulated doses of 23 +/- 8 Gy to the lung before death at 5.4 +/- 1.7 years after exposure. Dogs exposed repeatedly received a total alveolar deposition of 5.3 +/- 0.9 kBq/kg body mass during 7 to 10 semiannual exposures and accumulated doses of 22 +/- 5 Gy to the lung before death at 4.9 +/- 0.7 years after first exposure. Clearance of the plutonium from the lung in the dogs exposed repeatedly was slower than in the dogs exposed once. All dogs in the repeated-exposure study and all but one dog in the single-exposure study died from radiation effects. Pulmonary fibrosis accounted for 72% of the radiation-related deaths in the single-exposure study and 87% in the repeated-exposure study. The remaining dogs died with pulmonary cancer. Based on total cumulative radiation dose, the times after exposure to death from radiation pneumonitis and pulmonary fibrosis were not significantly different for single and repeated exposures. Thus dose rate does not appear to be an important factor in predicting death from radiation pneumonitis or pulmonary fibrosis for dogs inhaling 239PuO2.     

Investigation on circular asymmetry of geographical distribution in cancer mortality of Hiroshima atomic bomb survivors based on risk maps: analysis of spatial survival data

While there is a considerable number of studies on the relationship between the risk of disease or death and direct exposure from the atomic bomb in Hiroshima, the risk for indirect exposure caused by residual radioactivity has not yet been fully evaluated. One of the reasons is that risk assessments have utilized estimated radiation doses, but that it is difficult to estimate indirect exposure. To evaluate risks for other causes, including indirect radiation exposure, as well as direct exposure, a statistical method is described here that evaluates risk with respect to individual location at the time of atomic bomb exposure instead of radiation dose. In addition, it is also considered to split the risks into separate risks due to direct exposure and other causes using radiation dose. The proposed method is applied to a cohort study of Hiroshima atomic bomb survivors. The resultant contour map suggests that the region west to the hypocenter has a higher risk compared to other areas. This in turn suggests that there exists an impact on risk that cannot be explained by direct exposure.     

The research background for risk assessment of ethylene oxide: aspects of dose

Data for relationships between in vivo doses inferred from levels of hemoglobin (Hb) or DNA adducts and administered (by inhalation or injection) doses of ethylene oxide (EO) in mice, rats and humans are reviewed. At low absorbed doses or dose rates these relationships appear to be linear, whereas at higher dose rates deviations from linearity due to saturation kinetics of detoxification and of DNA repair as well as certain toxic effects have to be allowed for. If these factors are taken into consideration, a rather consistent picture is obtained for animal studies, with a variation by less than a factor 2 between estimates of adduct level increments or in vivo dose increments per unit of administered dose. Although the value for in vivo dose per unit of exposure dose (ppm-hour) in humans is uncertain because of unreliable data for the time-weighted average exposure level, the most likely value for this relationship, supported by data for ethene, agrees with data for the rodents. In the animal species testis doses are approximately one-half of the blood doses inferred from Hb adducts.     

Osteosarcoma development following single inhalation exposure to americium-241 in beagle dogs

Young, mature Beagle dogs underwent single inhalation exposure to respirable aerosols of 241AmO2 to determine the radiation dose distribution to tissues. The dogs were serially sacrificed to assess the clearance of 241Am from the lung, the rate of translocation to internal organs, the pattern of retention in the organs, and the rates and modes of excretion. Americium dioxide was relatively soluble in the lung, leading to the translocation of significant quantities of 241Am to bone and liver, thus delivering radiation doses to these tissues nearly equal to that received by the lung. Osteoblastic osteosarcomas developed in four dogs surviving more than 1000 days after exposure. Histologically, all of the osteosarcomas were associated with areas of radiation osteodystrophy characterized by bone infarction, peritrabecular new bone formation, marrow fibrosis, and microresorptive cavities. The retention and translocation of inhaled 241Am in dogs is similar to that of man, indicating that 241Am inhaled by humans may potentially result in significant risk of bone tumor development.     

There is no safe dose of prions

Understanding the circumstances under which exposure to transmissible spongiform encephalopathies (TSEs) leads to infection is important for managing risks to public health. Based upon ideas in toxicology and radiology, it is plausible that exposure to harmful agents, including TSEs, is completely safe if the dose is low enough. However, the existence of a threshold, below which infection probability is zero has never been demonstrated experimentally. Here we explore this question by combining data and mathematical models that describe scrapie infections in mice following experimental challenge over a broad range of doses. We analyse data from 4338 mice inoculated at doses ranging over ten orders of magnitude. These data are compared to results from a within-host model in which prions accumulate according to a stochastic birth-death process. Crucially, this model assumes no threshold on the dose required for infection. Our data reveal that infection is possible at the very low dose of a 1000 fold dilution of the dose that infects half the challenged animals (ID50). Furthermore, the dose response curve closely matches that predicted by the model. These findings imply that there is no safe dose of prions and that assessments of the risk from low dose exposure are right to assume a linear relationship between dose and probability of infection. We also refine two common perceptions about TSE incubation periods: that their mean values decrease linearly with logarithmic decreases in dose and that they are highly reproducible between hosts. The model and data both show that the linear decrease in incubation period holds only for doses above the ID50. Furthermore, variability in incubation periods is greater than predicted by the model, not smaller. This result poses new questions about the sources of variability in prion incubation periods. It also provides insight into the limitations of the incubation period assay.     

Evaluation of the effect of dose rate and dose absorption on the long-term radiation consequences in rats chronically taking in 90Sr

The effects of exposure to 90Sr which was given with food with daily doses 18.5 kBq per animal for 1-12 months, 37 kBq per animal for 1-10 months, 74 kBq per animal for 1-8 months and 148 kBq per animal for 1-6 months on mortality patterns in unimbred white rats were investigated. Hazard models were used to evaluate dose rate and accumulated dose influence on radiation-related trends in mortality. The time-dependent risk of death from all causes and from osteosarcomas depended on the dose rate. The risk of death from causes other than osteosarcoma depended on the dose rate and the accumulated dose. To predict time-dependent risk of death it was better to use the least time to calculate the dose rate--1 day.     

Microscopic dose distribution around PuO2 particles in lungs of hamsters,rats, and dogs

Summary Syrian hamsters, Fischer rats and Beagle dogs inhaled mono-disperse aerosols of PuO₂ and were scarificed during the first 16 days after exposure. The microscopic distribution of radiation dose and tissue-at-risk to alpha irradiation around individual particles in lung was studied using autoradiographs of lung tissue sections. The dose distributions in dogs and rats were more diffuse than in hamsters. A slightly greater tumor incidence was calculated for rats and dogs than for hamsters on the basis of dose distribution using the same dose-effect model for all three species. The small differences in tumor incidence predicted on this basis do not explain the extremely large differences in tumor incidences observed in these species after inhalation of PuO₂.Research performed under U.S. Department of Energy Contract Number DE-AC04-76EV01013. Research conducted in facilities fully accredited by the American Association for the Accreditation of Laboratory Animal Care     

Quantitative analysis of biological responses to ionizing radiation, including dose, irradiation time, and dose rate

Because biological responses to radiation are complex processes that depend on both irradiation time and total dose, consideration of both dose and dose rate is necessary to predict the risk from long-term irradiations at low dose rates. Here we mathematically and statistically analyzed the quantitative relationships between dose, dose rate and irradiation time using micronucleus formation and inhibition of proliferation of human osteosarcoma cells as indicators of biological response. While the dose-response curves did not change with exposure times of less than 20 h, at a given dose, both biological responses clearly were reduced as exposure time increased to more than 8 days. These responses became dependent on dose rate rather than on total dose when cells were irradiated for 20 to 27 days. Mathematical analysis demonstrates that the relationship between effective dose and dose rate is well described by an exponential function when the logarithm of effective dose is plotted as a function of the logarithm of dose rate. These results suggest that our model, the modified exponential (ME) model, can be applied to predict the risk from exposure to low-dose/low-dose-rate radiation.     

Single inhalation exposure to 90SrCl2 in the beagle dog: hematological effects

The toxicity of 90Sr administered by the inhalation route was studied in young adult Beagle dogs exposed once to aerosols containing 90SrCl2. Due to its relatively soluble chemical form, 90Sr was rapidly translocated from lung to bone where a substantial portion was retained for a long period of time. This resulted in only a brief radiation exposure of the respiratory tract and a protracted exposure of the skeleton. The long-term retained burdens ranged from 0.037 to 4.4 MBq 90Sr/kg body wt. Dogs were subsequently observed throughout their life span. Six dogs with long-term retained burdens of 1.7 to 4.1 MBq 90Sr/kg died at less than 32 days after exposure from radiation-induced bone marrow hypoplasia. Review of hematological parameters of all dogs showed a similar, consistent, and dose-related pancytopenia in those animals having a long-term retained burden of greater than 0.37 MBq 90Sr/kg. Thrombocytopenia and neutropenia persisted in all exposed dogs through 1000 days after exposure. For reference purposes, a burden of 0.37 MBq 90Sr/kg is calculated to deliver an average radiation dose to the skeleton over 30, 100, and 1000 days after intake of 1.0, 2.8, and 17 Gy, respectively. The hematologic changes were similar to those seen in people exposed to high doses of whole-body external radiation.     

A model for early death caused by radiation pneumonitis and pulmonary fibrosis after inhaling insoluble radioactive particles

Large radiation doses to the lung can cause early death from cardiopulmonary insufficiency resulting from radiation pneumonitis and pulmonary fibrosis. A model for early death following inhalation of insoluble radioactive particles is propose. The model is based on three assumptions: (1) early death results from damage to a cluster of cells from a large number of cell clusters at risk, (2) the dose that causes early death depends on how the radiation is delivered in time and (3) the cell clusters at risk to damage are equally sensitive ro radiation. Results from asymptotic theory of extreme values, along with biophysical considerations, suggest that the cumultive distribution function for the absorbed radiation dose to the production of pulmonary injury sufficient to cause early death is best estimated by the third asymptotic distribution without a threshold. This distribution function is identical to the Weibull cumulative distribution function. Data for Beagle dogs after inhaling relatively insoluble forms of alpha- or beta-gamma-emitting particles are shown to support the Weibull model.     

Cancer risk from chronic exposures to chemicals and radiation: a comparison of the toxicological reference value with the radiation detriment

This article aims at comparing reference methods for the assessment of cancer risk from exposure to genotoxic carcinogen chemical substances and to ionizing radiation. For chemicals, cancer potency is expressed as a toxicological reference value (TRV) based on the most sensitive type of cancer generally observed in animal experiments of oral or inhalation exposure. A dose–response curve is established by modelling experimental data adjusted to apply to human exposure. This leads to a point of departure from which the TRV is derived as the slope of a linear extrapolation to zero dose. Human lifetime cancer risk can then be assessed as the product of dose by TRV and it is generally considered to be tolerable in a 10^–6–10^–4 range for the public in a normal situation. Radiation exposure is assessed as an effective dose corresponding to a weighted average of energy deposition in body organs. Cancer risk models were derived from the epidemiological follow-up of atomic bombing survivors. Considering a linear-no-threshold dose-risk relationship and average baseline risks, lifetime nominal risk coefficients were established for 13 types of cancers. Those are adjusted according to the severity of each cancer type and combined into an overall indicator denominated radiation detriment. Exposure to radiation is subject to dose limits proscribing unacceptable health detriment. The differences between chemical and radiological cancer risk assessments are discussed and concern data sources, extrapolation to low doses, definition of dose, considered health effects and level of conservatism. These differences should not be an insuperable impediment to the comparison of TRVs with radiation risk, thus opportunities exist to bring closer the two types of risk assessment.

     

Specific parameters for the calculation of dose after aerosol inhalation of transuranium elements

A review on specific parameter measurements to calculate doses per unit of incorporation according to recommendations of the International Commission of Radiological Protection has been performed for inhaled actinide oxides. Alpha activity distribution of the particles can be obtained by autoradiography analysis using aerosol sampling filters at the work places. This allows us to characterize granulometric parameters of "pure" actinide oxides, but complementary analysis by scanning electron microscopy is needed for complex aerosols. Dissolution parameters with their standard deviation are obtained after rat inhalation exposure, taking into account both mechanical lung clearance and actinide transfer to the blood estimated from bone retention. In vitro experiments suggest that the slow dissolution rate might decrease as a function of time following exposure. Dose calculation software packages have been developed to take into account granulometry and dissolution parameters as well as specific physiological parameters of exposed individuals. In the case of poorly soluble actinide oxides, granulometry and physiology appear as the main parameters controlling dose value, whereas dissolution only alters dose distribution. Validation of these software packages are in progress.     

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.     

Radiation dose and second cancer risk in patients treated for cancer of the cervix

The risk of cancer associated with a broad range of organ doses was estimated in an international study of women with cervical cancer. Among 150,000 patients reported to one of 19 population-based cancer registries or treated in any of 20 oncology clinics, 4188 women with second cancers and 6880 matched controls were selected for detailed study. Radiation doses for selected organs were reconstructed for each patient on the basis of her original radiotherapy records. Very high doses, on the order of several hundred gray, were found to increase the risk of cancers of the bladder [relative risk (RR) = 4.0], rectum (RR = 1.8), vagina (RR = 2.7), and possibly bone (RR = 1.3), uterine corpus (RR = 1.3), cecum (RR = 1.5), and non-Hodgkin's lymphoma (RR = 2.5). For all female genital cancers taken together, a sharp dose-response gradient was observed, reaching fivefold for doses more than 150 Gy. Several gray increased the risk of stomach cancer (RR = 2.1) and leukemia (RR = 2.0). Although cancer of the pancreas was elevated, there was no evidence of a dose-dependent risk. Cancer of the kidney was significantly increased among 15-year survivors. A nonsignificant twofold risk of radiogenic thyroid cancer was observed following an average dose of only 0.11 Gy. Breast cancer was not increased overall, despite an average dose of 0.31 Gy and 953 cases available for evaluation (RR = 0.9); there was, however, a weak suggestion of a dose response among women whose ovaries had been surgically removed. Doses greater than 6 Gy to the ovaries reduced breast cancer risk by 44%. A significant deficit of ovarian cancer was observed within 5 years of radiotherapy; in contrast, a dose response was suggested among 10-year survivors. Radiation was not found to increase the overall risk of cancers of the small intestine, colon, ovary, vulva, connective tissue, breast, Hodgkin's disease, multiple myeloma, or chronic lymphocytic leukemia. For most cancers associated with radiation, risks were highest among long-term survivors and appeared concentrated among women irradiated at relatively younger ages.     

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.     

Retrospective biodosimetry among United States radiologic technologists

Measurement of chromosome translocations in peripheral blood lymphocytes has been used to quantify prior exposure to ionizing radiation, including for workers exposed to low, chronic doses. We assessed translocation frequencies in a subset of U.S. radiologic technologists to substantiate ionizing radiation dose estimates developed for 110,418 technologists who worked between 1916 and 1984. From 3,441 cohort members known to have begun working before 1950, we selected a sample of 152, stratified by estimated cumulative dose, over-sampling from higher-dose categories and excluding persons with a prior cancer diagnosis, a personal or family history of chromosomal instability disorders, or a current history of smoking. Estimates of film-badge dose ranged from less than 10 cSv to more than 30 cSv. Blood samples, obtained in 2004, were analyzed by fluorescence in situ hybridization (FISH) whole chromosome painting by simultaneously labeling chromosomes 1, 2 and 4 in red and 3, 5 and 6 in green. Translocations were scored in 1800 well-spread metaphase cells and expressed per 100 cell equivalents (CE) per person. Linear Poisson regression models with allowance for overdispersion were used to assess the relationship between estimated occupational red bone marrow absorbed dose in cGy and translocation frequency, adjusted for age, gender and estimated red bone marrow absorbed dose score from personal diagnostic procedures. We observed 0.09 excess translocations per 100 CE per cGy red bone marrow dose (95% CI: -0.01, 0.2; P = 0.07), which is similar to the expected estimate based on previous cytogenetic studies (0.05 excess translocations per 100 CE per cGy). Despite uncertainty in the estimates of occupational red bone marrow absorbed doses, we found good general agreement between the doses and translocation frequencies, lending support to the credibility of the dose assessment for this large cohort of U.S. radiologic technologists.     

Heritability and segregation analysis of osteosarcoma in the Scottish deerhound

Osteosarcoma is the most common malignant bone tumor in dogs and, like its human orthologue, is characterized by aggressive local behavior and high metastatic rates. The Scottish deerhound is a breed of dog with a >15% incidence of osteosarcoma and represents an excellent spontaneously occurring large-animal model of the human disease. We modeled the transmission of the osteosarcoma phenotype in a population of over 1000 related deerhounds ascertained as part of a prospective health study. Variance component analysis, segregation analysis, and linear modeling were performed to evaluate heritability, to infer the presumptive transmission model, and to identify covariate effects for this phenotype within the breed, respectively. Based on variance component analysis, heritability (h2) was estimated to be 0.69. Six transmission models were analyzed by segregation analysis; based on Akaike's information criteria, the most parsimonious model was the Mendelian major gene model with dominant expression. Linear modeling identified gender and genotype as significant predictors of disease outcome. Importantly, duration of gonadal hormone exposure, weight, and height at maturity were not significant predictors of outcome. Inheritance of the putative high-risk allele was thus associated with >75% risk of disease occurrence compared to the <5% baseline risk. These results support the hypothesis that a major gene with a dominant effect explains most of the osteosarcoma phenotype within the Scottish deerhound.