Life shortening in mice exposed to fission neutrons and gamma rays. V. Further studies with single low doses

Data are presented on the mean after survival of female B6CF1 mice exposed to single doses of neutrons (1 to 40 rad) or gamma rays (22.5, 45, and 90 rad). For gamma-ray exposures and for neutron exposures up to 10 rad, the dose-response curves are indistinguishable from linear; higher neutron doses produce significant departures and linearity. Consequently, in these data, an upper limit of the relative biological effectiveness (RBE) exists for life shortening from all causes of death after single neutron exposures; this value is 15.0 +/- 5.1. The RBE depends on the cause of death, ranging from 2 to 5 for lymphoreticular tumors to 23-24 for lung tumors.     

On the shape of neutron dose-effect curves for radiogenic cancers and life shortening in mice

Male and female hybrid BCF₁ (C57BL/6 BdxBALB/c Bd) were exposed to total neutron doses of 0.06, 0.12, 0.24, and 0.48 Gy in fractions over a period of 24 weeks. The fractionation regimens were: 24 weekly fractions of 0.0025 Gy, 12 fractions of 0.01 Gy every 2 weeks, 6 fractions of 0.04 Gy every 4 weeks, and 3 fractions of 0.16 Gy every 8 weeks. In order to detect any change in susceptibility with age over the period of exposures from 16 weeks to 40 weeks of age, mice were exposed to single doses of 0.025, 0.05, 0.10, and 0.2 Gy at 16 and 40 weeks of age. These experiments were designed to test whether the initial parts of the dose-response relationships for life shortening and cancer induction could be determined economically by using fractionated exposures and whether or not the initial slopes were linear. The conclusions were that for life shortening and most radiogenic cancers, the dose-effect curves are linear and that fractionation of the neutron dose has no effect on the magnitude of the response of equal total doses over the range of doses studied. The ratio of such initial slopes and comparable linear initial slopes for a reference radiation should provide maximum and constant relative biological effectiveness values.     

Dose-response modeling of life shortening in a retrospective analysis of the combined data from the JANUS program at Argonne National Laboratory

Life shortening was investigated in both sexes of the B6CF1 (C57BL/6 x BALB/c) mouse exposed to fission neutrons and 60Co gamma rays. Three basic exposure patterns for both neutrons and gamma rays were compared: single exposures, 24 equal once-weekly exposures, and 60 equal once-weekly exposures. Ten different dose-response models were fitted to the data for animals exposed to neutrons. The response variable used for all dose-response modeling was mean after-survival. A simple linear model adequately described the response to neutrons for females and males at doses less than or equal to 80 cGy. At higher neutron dose levels a linear-quadratic equation was required to describe the life-shortening response. An effect of exposure pattern was observed prior to the detection of curvature in the dose response for neutrons and emerged as a potentially significant factor at neutron doses in the range of 40-60 cGy. Augmentation of neutron injury with dose protraction was observed in both sexes and began at doses as low as 60 cGy. The life-shortening response for all animals exposed to gamma rays (22-1918 cGy) was linear and inversely dependent upon the protraction period (1 day, 24 weeks, 60 weeks). Depending on the exposure pattern used for the gamma-ray baseline, relative biological effectiveness (RBE) values ranged from 6 to 43. Augmentation, because it occurred only at higher levels of neutron exposure, had no influence on the estimation of RBEm.     

Cancer mortality risk among workers at the Mayak nuclear complex

At present, direct data on risk from protracted or fractionated radiation exposure at low dose rates have been limited largely to studies of populations exposed to low cumulative doses with resulting low statistical power. We evaluated the cancer risks associated with protracted exposure to external whole-body gamma radiation at high cumulative doses (the average dose is 0.8 Gy and the highest doses exceed 10 Gy) in Russian nuclear workers. Cancer deaths in a cohort of about 21,500 nuclear workers who began working at the Mayak complex between 1948 and 1972 were ascertained from death certificates and autopsy reports with follow-up through December 1997. Excess relative risk models were used to estimate solid cancer and leukemia risks associated with external gamma-radiation dose with adjustment for effects of plutonium exposures. Both solid cancer and leukemia death rates increased significantly with increasing gamma-ray dose (P < 0.001). Under a linear dose-response model, the excess relative risk for lung, liver and skeletal cancers as a group (668 deaths) adjusted for plutonium exposure is 0.30 per gray (P < 0.001) and 0.08 per gray (P < 0.001) for all other solid cancers (1062 deaths). The solid cancer dose-response functions appear to be nonlinear, with the excess risk estimates at doses of less than 3 Gy being about twice those predicted by the linear model. Plutonium exposure was associated with increased risks both for lung, liver and skeletal cancers (the sites of primary plutonium deposition) and for other solid cancers as a group. A significant dose response, with no indication of plutonium exposure effects, was found for leukemia. Excess risks for leukemia exhibited a significant dependence on the time since the dose was received. For doses received within 3 to 5 years of death the excess relative risk per gray was estimated to be about 7 (P < 0.001), but this risk was only 0.45 (P = 0.02) for doses received 5 to 45 years prior to death. External gamma-ray exposures significantly increased risks of both solid cancers and leukemia in this large cohort of men and women with occupational radiation exposures. Risks at doses of less than 1 Gy may be slightly lower than those seen for doses arising from acute exposures in the atomic bomb survivors. As dose estimates for the Mayak workers are improved, it should be possible to obtain more precise estimates of solid cancer and leukemia risks from protracted external radiation exposure in this cohort.     

Seventeen-year mortality experience of proton radiation in Macaca mulatta

This is an interim report on the lifetime study of chronic mortality and its causes under investigation in 31 control (20 males, 11 females) and 217 survivors (124 males, 93 females) of an acute 90-day experiment in rhesus monkeys. Single acute whole-body exposures were made using 32-, 55-, 138-, 400-, and 2300-MeV protons in 1964-1965. Doses ranged from 25 to 800 rad and dose rates from 12.5 and 100 rad per minute. Tissue depths of partially penetrating 32- and 55-MeV particles were approximately 1 and approximately 2.5 cm, respectively, and depth doses at the respective distances were 115 and 122% of surface doses. Protons with energies greater than or equal to 138 MeV were totally penetrating and the depth doses were essentially homogenous. For pooled data: (1) mortality was significantly higher (P less than 0.01) in irradiated animals (48%) than in controls (19%); (2) mortality in animals exposed to partially penetrating 55-MeV protons (53%) was essentially similar to those given totally penetrating 138- (53%), 400- (49%), and 2300-MeV (44%) exposures; (3) proton energies and doses that were effective in producing life shortening were greater than or equal to 55 MeV and greater than or equal to 360-400 rad, respectively; (4) death rates for irradiated animals compared to controls began to increase after approximately 8 years, approximately 2 years, and approximately 1 year for those exposed to 360-400, 500-650, and 800 rad, respectively; (5) of the nine probable causes of death reported, the leading causes were primary infections in both irradiated (31%) and control (50%) animals, endometriosis (25% vs 0%, respectively), neoplasms (17% vs 0%), and organ degeneration (17% vs 33%); and (6) if endometriosis is included with the neoplastic group, deaths from all forms of neoplasms would be 42% in irradiated animals.(ABSTRACT TRUNCATED AT 400 WORDS)     

Chromosome rearrangements from spermatogonial chronic neutron irradiation in mice.

Adult male mice were given a range of neutron doses at 80 +/- 20 mrad/h from a plutonium-beryllium source. Cytogenetic analysis indicated that chronic spermatogonial exposure to a mean total dose of 10, 30, 52, 98 or 150 rad produced translocations, sampled in spermatocytes four months later, amounting to 0.32, 0.99. 1.69, 1.91 and 1.65%, respectively. The dose response for the 0-52 rad range was linear. For higher doses, a better fit to the data was an expression with dose exponent above unity.     

Radiation effects on breast cancer risk: a pooled analysis of eight cohorts

Breast cancer incidence rates after radiation exposure in eight large cohorts are described and compared. The nature of the exposures varies appreciably, ranging from a single or a small number of high-dose-rate exposures (Japanese atomic bomb survivors, U.S. acute post-partum mastitis patients, Swedish benign breast disease patients, and U.S. infants with thymic enlargement) to highly fractionated high-dose-rate exposures (two U.S. tuberculosis cohorts) and protracted low-dose-rate exposure (two Swedish skin hemangioma cohorts). There were 1,502 breast cancers among 77,527 women (about 35,000 of whom were exposed) with 1.8 million woman-years of follow-up. The excess risk depends linearly on dose with a downturn at high doses. No simple unified summary model adequately describes the excess risks in all groups. Excess risks for the thymus, tuberculosis, and atomic bomb survivor cohorts have similar temporal patterns, depending on attained age for relative risk models and on both attained age and age at exposure for excess rate models. Excess rates were similar in these cohorts, whereas, related in part to the low breast cancer background rates for Japanese women, the excess relative risk per unit dose in the bomb survivors was four times that in the tuberculosis or thymus cohorts. Excess rates were higher for the mastitis and benign breast disease cohorts. The hemangioma cohorts showed lower excess risks suggesting ameliorating dose-rate effects for protracted low-dose-rate exposures. For comparable ages at exposure (approximately 0.5 years), the excess risk in the hemangioma cohorts was about one-seventh that in the thymus cohort, whose members received acute high-dose-rate exposures. The results support the linearity of the radiation dose response for breast cancer, highlight the importance of age and age at exposure on the risks, and suggest a similarity in risks for acute and fractionated high-dose-rate exposures with much smaller effects from low-dose-rate protracted exposures. There is also a suggestion that women with some benign breast conditions may be at elevated risk of radiation-associated breast cancer.     

Chromosome aberrations induced in human lymphocytes by radiation from 252Cf.

In vitro dose--response curves of unstable chromosome aberrations in human lymphocytes have been obtained for 252Cf neutron radiation. The aberration yields fitted best to the linear function Y=aD, which is consistent with the single-track model of aberration formation for high LET radiation. The curves have been compared with others previously produced in this laboratory for several energies of neutrons and for 60Co gamma radiation. The r.b.e. for 252Cf with respect to 60Co is 27 at very low doses, decreasing to 6 at an aberration yield equivalent to 400 rad of 18 rad/hour gamma radiation. A profile of chromosome-aberration induction with depth in a perspex phantom was obtained by placing blood samples at several distances over the range 0.65-2.0 cm from the californium source. This profile was compared with depth-damage calculations for a radium needle. The r.b.e. of 252Cf radiation relative to 226Ra gamma radiation increased with the distance from the source, implying that californium is more effective at greater distances in destroying the ability of cells to divide, which may be an advantage in the treatment of large tumours.     

The effects of a fractionated gamma irradiation on life shortening and disease incidence in BALB/c mice

BALB/c male mice (12 weeks old) were exposed to a single or fractionated exposure of 137Cs gamma rays. The fractionated dose was split into 10 equal doses delivered at an interval of 1 day. The causes and possible causes of spontaneous death were ascertained by autopsy and histological examination, and the data were treated by competing risk analysis. Life shortening followed a linear dose dependency and was about the same for fractionated (38.1 +/- 3.1 days/Gy) as for single (46.2 +/- 4.3 days/Gy) exposure. Death from tumor disease was enhanced and that from nonstochastic lung and kidney diseases was reduced after fractionated compared to single exposure.     

Radiation carcinogenesis: time-dose relationships

The present studies were undertaken to examine the time-dose relationships for the induction of lung adenocarcinomas and mammary adenocarcinomas in female BALB/c mice following gamma irradiation. Twelve-week-old female BALB/c/An NBd mice were irradiated with 137Cs gamma rays, and lifetime tumor incidences following high-dose-rate, low-dose-rate, or fractionated exposure regimens were compared. Analysis of the results indicated that the data could be fitted by linear-quadratic dose-response models for the induction of both tumors following acute doses and a linear model with a slope similar to that for the linear portion of the linear quadratic following low-dose-rate exposure regimens. When doses were fractionated the response was dependent upon the dose per fraction. If the dose per fraction was a dose which was predominantly on the linear portion of the acute dose response curve, then the response was linear and similar to that after low-dose-rate exposures. If the dose per fraction was in a region where the quadratic portion of the acute dose-response was significant, then the tumor incidence was higher than that following low-dose-rate exposures.     

Life shortening in mice exposed to fission neutrons and gamma rays. VI. Studies with the white-footed mouse, Peromyscus leucopus

Some of the studies on late effects of neutron and gamma radiation previously carried out with the C57BL6 X BALB/c F1 hybrids of Mus musculus have been repeated with the white-footed mouse, Peromyscus leucopus, a cricetid rodent of a different subfamily, with differing physiological characteristics and a different spectrum of pathologies. Among the more important findings were the following: For both species, the life shortening per rad at low doses of either radiation was the same percentage of the life span. The limiting values of the relative biological effectiveness for life shortening from all causes of death were about the same for the two species, ranging from 8 to 16, depending on the method of calculation. Fractionated neutron exposures failed to produce significant life shortening in Peromyscus over that observed at single doses. Tumor-related deaths accounted for at least 70 to 75% of the radiation-specific excess mortality in Peromyscus.     

Fractionated, low-dose-rate ionizing radiation exposure and chronic ulcerative dermatitis in normal and Trp53 heterozygous C57BL/6 mice

The influence of low-dose-rate chronic radiation exposure and adaptive responses on non-cancer diseases is largely unknown. We examined the effect of low-dose/low-dose-rate fractionated or single exposures on spontaneous chronic ulcerative dermatitis in Trp53 normal or heterozygous female C57BL/6 mice. From 6 weeks of age, mice were exposed 5 days/week to single daily doses (0.33 mGy, 0.7 mGy/h) totaling 48, 97 or 146 mGy over 30, 60 or 90 weeks, and other Trp53+/- mice were exposed to a single dose of 10 mGy (0.5 mGy/min) at 20 weeks of age. The 90-week exposure produced an adaptive response, decreasing both disease frequency and severity in Trp53+/+ mice and extending the life span of older animals euthanized due to severe disease. The 30- or 60-week exposures had no significant protective or detrimental effect. In contrast, the chronic, fractionated exposure for 30 or 60 weeks significantly increased the frequency and severity of the disease in older Trp53+/- mice, significantly decreasing the life span of the animals required to be euthanized for disease. Similarly, the single 10-mGy exposure also increased disease frequency in older animals. However, the chronic, fractionated exposure for 90 weeks prevented these detrimental effects, with disease frequency and severity not different from unexposed controls. We conclude that very low-dose fractionated exposures can induce a protective adaptive response in both Trp53 normal and heterozygous mice, but that a lower threshold level of exposure, similar in both cases, must first be passed. In mice with reduced Trp53 functionality, doses below the threshold can produce detrimental effects.     

Epidemiological studies of cataract risk at low to moderate radiation doses: (not) seeing is believing

The prevailing belief for some decades has been that human radiation-related cataract occurs only after relatively high doses; for instance, the ICRP estimates that brief exposures of at least 0.5-2 Sv are required to cause detectable lens opacities and 5 Sv for vision-impairing cataracts. For protracted exposures, the ICRP estimates the corresponding dose thresholds as 5 Sv and 8 Sv, respectively. However, several studies, especially in the last decade, indicate that radiation-associated opacities occur at much lower doses. Several studies suggest that medical or environmental radiation exposure to the lens confers risk of opacities at doses well under 1 Sv. Among Japanese A-bomb survivors, risks for cataracts necessitating lens surgery were seen at doses under 1 Gy. The confidence interval on the A-bomb dose threshold for cataract surgery prevalence indicated that the data are compatible with a dose threshold ranging from none up to only 0.8 Gy, similar to the dose threshold for minor opacities seen among Chernobyl clean-up workers with primarily protracted exposures. Findings from various studies indicate that radiation risk estimates are probably not due to confounding by other cataract risk factors and that risk is seen after both childhood and adult exposures. The recent data are instigating reassessments of guidelines by various radiation protection bodies regarding permissible levels of radiation to the eye. Among the future epidemiological research directions, the most important research need is for adequate studies of vision-impairing cataract after protracted radiation exposure.     

Effects of Substerilization Doses of Co60 Gamma Radiation on the Cold-Storage Life Extension of Shucked Soft-Shelled Clams and Haddock Fillets

Total aerobic-facultative and anaerobic (clostridia) macrocolony count data are presented, with analysis and interpretation, for both haddock fillets and shucked soft-shelled clams which received doses of from 50,000 to 800,000 rad of Co⁶⁰ gamma rays. These data indicated that haddock fillets may be maintained in good condition at refrigeration temperatures above freezing for about 1 week at 6 C, and approximately 2 weeks at 0 C, when treated with from 50,000 to 150,000 rad of ionizing radiation. In the dose range from 200,000 to 350,000 rad, the storage life may be extended up to some 2 weeks at 6 C, and 3 weeks at 0 C. Treatments in the dose range from 400,000 to 500,000 rad may defer spoilage for about 1 month, and doses of 550,000 to 650,000 rad afford protection against bacterial spoilage up to approximately 1.5 months. At the high substerilization doses of 700,000 to 800,000 rad, haddock fillets may be held for from 2 to 3 months in refrigerated storage before becoming unfit for marketing and consumption. Shucked soft-shelled clams can be held for about 2.5 weeks at 0 C and close to 12 days at 6 C, when given low substerilization doses of from 50,000 to 150,000 rad of ionizing radiation. At doses of from 200,000 to 350,000 rad, the clams may be preserved effectively for periods up to 3 weeks at 0 or 6 C, and some 6 weeks at these temperatures with doses of about 450,000 rad. With treatments of 500,000 to 600,000 rad, the storage life may be extended for some 2 months, and at doses of 650,000 to 800,000 rad the shucked clams remain in a good state of preservation for up to 3 months at temperatures of 0 to 6 C. Thus, it would appear that shucked soft-shelled clams may be maintained for significantly longer periods in refrigerated storage than haddock fillets when the same radiation treatments are applied to each product. Clostridia levels in both products were relatively low initially, and were reduced significantly by the gamma rays at the doses studied. Moreover, those clostridia that survived the radiation treatments were found to remain at safe, low levels during the various periods in refrigerated storage employed for these products, a very encouraging result from the public health, as well as commercial, standpoint.     

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.     

Neoplastic transformation is enhanced by multiple low doses of fission-spectrum neutrons

The neoplastic transformation of C3H mouse 10T1/2 cells was measured induced by fission-spectrum neutrons delivered at a high dose rate in five fractions over 4 days. The transformation frequency was significantly enhanced over that due to single equivalent total doses. These new data, in the low dose region, demonstrate an increased transformation frequency by fractionated versus single exposures of high-dose-rate fission-spectrum neutrons; an increase equal to that observed with low-dose-rate fission-spectrum neutrons (i.e., 0.086 rad/min). Estimates of the dose modifying factor (DMF), based upon the ratio of the initial linear portions of the induction curves for high and for low dose rates, suggest the same DMF (approximately 7.8) for both five daily fractions of high-dose-rate neutrons and for low-dose-rate neutrons. However, when these results are compared to those following high-dose-rate 60Co gamma rays (100 rad/min), the relative biological effectiveness (RBE) for low-dose-rate fission-spectrum neutrons based upon slope ratios is 19.6; similarly, the RBE relative to five daily fractions of 60Co gamma rays is 78.8.     

Neutron RBEs and the radiosensitive target for mouse immature oocyte killing

The highly radiosensitive immature oocytes of mice were irradiated in vivo with graded doses of 252Cf fission radiation, 0.43- or 15-MeV neutrons, or 60Co gamma rays. Comparisons of oocyte survival for neutrons and for gamma rays demonstrate that neutron RBEs for the killing of these important cells do not reach the high values (30-50 or more) at low doses observed for several other biological end points. Rather, neutrons differ little in effectiveness from gamma rays in killing these extremely sensitive murine oocytes. For 0.43-MeV neutrons, RBEs obtained from fitted survival curves reach only 1.7 at 0.1 rad. For 15-MeV neutrons, they are not significantly different from 1 at any dose tested (lowest, 4.5 rad). For 252Cf fission neutrons (E = 2.15 MeV), RBEs are intermediate between those for 0.43- and 15-MeV neutrons. For all neutron energies tested, the RBEs are particularly low in the juvenile period, a time when murine immature oocytes are especially radiosensitive. With exposure just prior to birth, however, when these cells are much less easily killed, higher, more usual RBEs are found. The minimum size of the lethality target in mouse immature oocytes, estimated from the inactivation constant for 0.43-MeV neutrons and microdosimetric values, is larger than the nucleus but not larger than the cell. This and related analytical considerations suggest that the hypersensitive target in these particular oocytes is the plasma membrane, a finding which is in excellent accord with results from other experiments using different, contrasting radiations and dose deliveries (accelerated Si14+ ions, gamma rays, and beta rays from 3HOH compared with those from [3H]thymidine).     

Split-dose recovery for radiation-induced tumours in rat skin.

Tumour-related recovery in rat skin was estimated from the dependence of tumour yield on time between split doses of electron radiation. Tumour yield versus dose was established at nine dose points, and at three points the dose was split into two equal fractions spaced 0-25, 3-2 or 6-3 hours apart. After irradiation the rats were observed periodically for at least 64 weeks, and at death the tumours were examined histologically. The dependence of yield on dose for single doses was consistent with a quadratic function up to a peak yield at about 1600 rad. The effect of split doses on tumour yield depended on the position on the dose--response curve. At the lowest split dose, the yield declined with a half-time of about 1-8 hours. At the intermediate split dose, an initial increase was followed by a decline with a half-time of about 3-9 hours. At the highest split dose, the tumour yield increased with time between exposures. Fractionation-induced increases in tumour yield were explained as a sparing effect on cell lethality, whereas tumour-related recovery per se was indicated at the lower two doses.     

Radiation-induced chromosome aberrations in lymphocytes from man and crab-eating monkey: The dose-response relationships at low doses

To obtain information on the relation beteween yiels of chrmosome aberrations and dose at low-dose levels, experiments were conducted with 5, 10, 20, 30 and 50 rad of ¹³⁷Cs γ-rays, on lymphocytes from man and crab-eating monkey (Macaca fascicularis). The dose-response relationship for dicentrics was obtained from the combined data of these low-dose experiments with those of our previous onse at high doses (100–400 rad) When the difference between observed yields and those expected from the linear-quadratic model were computed, the dose-response curve had a good fit for man, but not for the monkey. The linear regression lines between 0 and 30 rad were calculated, because the expected values of α/β for man and monkey would be about 100 and 60 rad.The human date gave a satisfactory fit to a linear model, i.e., a linear increase in aberration frequency with dose, whereas this was not so for those of the monkey. Furtyhermose, there was some suggestive evidence for the existence of plateau in dicentrics yields between 10 and 30 rad for the monkey and between 20 and 30 rad for human lymphocytes, but more data would be needed to verify this suggestion, particularly for human lymphocytes.