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)     

Late cataractogenesis in rhesus monkeys irradiated with protons and radiogenic cataract in other species

Rhesus monkeys (Macaca mulatta) which were irradiated at ca. 2 years of age with acute doses (less than or equal to 5 Gy) of protons (32-2300 MeV) are exhibiting the late progressive phase of radiation cataractogenesis 20-24 years after exposure, the period during which we have been monitoring the sequelae of irradiation of the lens. The median life span of the primate is approximately 24 years. Analogous late ocular changes also occur in a similar period of the lifetimes of New Zealand White (NZW) rabbits (Oryctolagus cuniculus) exposed at 8-10 weeks of age to 460-MeV 56Fe ions. In this experiment, which has been in progress for ca. 6 years, we are following the development of radiation-induced lenticular opacification (cataractogenic profiles) throughout the life span. The median life span of the lagomorph is 5-7 years. Cataractogenic profiles for NZW rabbits irradiated with 20Ne and 40Ar ions and 60Co gamma photons were obtained previously. Reference is also made to measurements of the cataractogenic profiles of a short-lived rodent, the Fischer 344 rat (Rattus norvegicus) during the first year after exposure at 8-10 weeks of age to spread-Bragg-peak protons of 55 MeV nominal energy. The median life span of the rodent is reported to be 2-3 years.     

Updates to astronaut radiation limits: radiation risks for never-smokers

New epidemiology assessments of the life span study (LSS) of the atomic bomb survivors in Japan and of other exposed cohorts have been made by the U.S. National Academy of Sciences, the United Nations Committee on the Effects of Atomic Radiation, and the Radiation Research Effects Foundation in Japan. The National Aeronautics and Space Administration (NASA) uses a 3% risk of exposure-induced death (REID) as a basis for setting age- and gender-specific dose limits for astronauts. NASA's dose limits originate from the report of the National Council on Radiation Protection and Measurements (NCRP) in the year 2000 based on analysis of older epidemiology data. We compared the results of the recent analysis of the LSS to the earlier risk projections from the NCRP. Using tissue-specific, incidence-based risk transfer from the LSS data to a U.S. population to project REID values leads to higher risk and reduced dose limits for older astronauts (>40 years) compared to earlier models that were based on mortality risk transfer. Because astronauts and many other individuals should be considered as healthy workers, including never-smokers free of lifetime use of tobacco, we considered possible variations in risks and dose limits that would occur due to the reference population used for estimates. After adjusting cancer rates to remove smoking effects, radiation risks for lung and total cancer were estimated using a mixture model, with equal weights for additive and multiplicative transfer, to be 20% and 30% lower for males and females, respectively, for never-smokers compared to the average U.S. population. We recommend age- and gender-specific dose limits based on incidence-based risk transfer for never-smokers that could be used by NASA. Our analysis illustrates that gaining knowledge to improve transfer models, which entail knowledge of cancer initiation and promotion effects, could significantly reduce uncertainties in risk projections.     

Using electron beam radiation to simulate the dose distribution for whole body solar particle event proton exposure

As a part of the near solar system exploration program, astronauts may receive significant total body proton radiation exposures during a solar particle event (SPE). In the Center for Acute Radiation Research (CARR), symptoms of the acute radiation sickness syndrome induced by conventional radiation are being compared to those induced by SPE-like proton radiation, to determine the relative biological effectiveness (RBE) of SPE protons. In an SPE, the astronaut’s whole body will be exposed to radiation consisting mainly of protons with energies below 50 MeV. In addition to providing for a potentially higher RBE than conventional radiation, the energy distribution for an SPE will produce a relatively inhomogeneous total body dose distribution, with a significantly higher dose delivered to the skin and subcutaneous tissues than to the internal organs. These factors make it difficult to use a ⁶⁰Co standard for RBE comparisons in our experiments. Here, 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 is described. In these studies, Monte Carlo simulation was used to determine the dose distribution of electron beam radiation in small mammals such as mice and ferrets as well as large mammals such as pigs. These studies will help to better define the topography of the time-dose-fractionation versus biological response landscape for astronaut exposure to an SPE.     

Radiation quality and rat motor performance

The effects of bremsstrahlung, electron, gamma, and neutron radiations were investigated on the motor performance of male Sprague-Dawley rats. Rats were irradiated at a midline tissue dose rate of 20 Gy/min +/- 1 with one of the following: 18.6-MeV electrons (N = 40) or 18.1-MVp bremsstrahlung (N = 57) from a linear accelerator, 60Co 1.25-MeV gamma-ray photons (N = 48), or reactor neutrons at 1.67 MeV tissue-kerma weighted-mean energy (N = 43). Radiation effects were determined by establishing median effective doses (ED50) for rats trained on an accelerod, a shock-avoidance motor performance test. ED50's were based on 10-min postexposure performance. The ED50's were 61 Gy for electrons, 81 Gy for bremsstrahlung, 89 Gy for gamma-ray photons, and 98 Gy for neutrons. In terms of relative biological effectiveness to produce early performance decrement (10 min from the start of irradiation), significant differences existed between the electrons and the other three fields and between the bremsstrahlung and neutron fields. These differences could not be explained by macroscopic dose distribution patterns in the irradiated animals. The data imply that different radiation qualities are not equally effective at disrupting performance, with high-energy electrons being the most effective and neutrons the least.     

Radiation protection: the NCRP guidelines and some considerations for the future.

The National Council on Radiation Protection and Measurements (NCRP) in the USA and the International Commission on Radiological Protection (ICRP), worldwide, were formed about 1928 and have since made recommendations on appropriate levels of protection from ionizing radiation for workers and for the public. These recommendations and much of the guidance provided by these organizations have usually been adopted by regulatory bodies around the world. In the case of the NCRP, the levels have fallen from 0.1 roentgen per day in 1934 to the current 5 rem per year (a factor of about 5). The present levels recommended by both the ICRP and the NCRP correspond to reasonable levels of risk where the risks of harm from ionizing radiation are compared with the hazards of other, commonly regarded, as safe, industries. Some considerations for the future in radiation protection include trends in exposure levels (generally downward for the average exposure to workers) and improvements in risk estimation; questions of lifetime limits, de minimis levels, and partial body exposures; plus problems of high LET radiations, acceptability of risk, synergisms, and risk systems for protection.     

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.     

Oncogenic transformation by fractionated doses of neutrons

Oncogenic transformation was assayed after C3H 10T1/2 cells were irradiated with monoenergetic neutrons; cells were exposed to 0.23-, 0.35-, 0.45-, 5.9-, and 13.7-MeV neutrons given singly or in five equal fractions over 8 h. At the biologically effective neutron energy of 0.45 MeV, enhancement of transformation was evident with some small fractionated doses (below 1 Gy). When transformation was examined as a function of neutron energy at 0.5 Gy, enhancement was seen for cells exposed to three of the five energies (0.35, 0.45, and 5.9 MeV). Enhancement was greatest for cells irradiated with 5.9-MeV neutrons. Of the neutron energies examined, 5.9-MeV neutrons had the lowest dose-averaged lineal energy and linear energy transfer. This suggests that enhancement of transformation by fractionated low doses of neutrons may be radiation-quality dependent.     

Dietary factors and cancer mortality among atomic-bomb survivors

Dietary factors such as fruit and vegetables are thought to reduce the risk of cancer incidence and mortality. We investigated the effect of a diet rich in fruit and vegetables against the long-term effects of radiation exposure on the risk of cancer. A cohort of 36,228 atomic-bomb survivors of Hiroshima and Nagasaki, for whom radiation dose estimates were currently available, had their diet assessed in 1980. They were followed for a period of 20 years for cancer mortality. The joint-effect of fruit and vegetables intake and radiation exposure on risk of cancer death was examined, in additive (sum of effects of diet alone and radiation alone) and multiplicative (product of effects of diet alone and radiation alone) models. In the additive model, a daily intake of fruit and vegetables significantly reduced the risk of cancer deaths by 13%, compared to an intake of once or less per week. Radiation exposure of 1 Sievert (Sv) increased significantly the risk of cancer death by 48-49%. The additive joint-effects showed a lower risk of cancer among those exposed to 1 Sv who had a diet rich in vegetables (49%-13%=36%) or fruit (48%-13%=35%). The multiplicative model gave similar results. The cancer risk reduction by vegetables in exposed persons went from 52% (effect of radiation alone) to 32% (product of effect of vegetables and radiation), and cancer risk reduction by fruit was 52% (radiation alone) to 34% (product of effect of fruit and radiation). There was no significant evidence to reject either the additive or the multiplicative model. A daily intake of fruit and vegetables was beneficial to the persons exposed to radiation in reducing their risks of cancer death.     

Mortality in the Children of Atomic Bomb Survivors and Controls

A continuing study of mortality rates among children born to survivors of the atomic bombings and a suitable group of controls has been updated; the average interval between birth and verification of death or survival is 17 years. The mortality experience is now based on 18,946 children liveborn to parents one or both of whom were proximally exposed, receiving jointly an estimated dose of 117 rem; 16,516 children born to distally exposed parents receiving essentially no radiation; and 17,263 children born to parents not in Hiroshima or Nagasaki at the time of the bombings. No clearly significant effect of parental exposure on child's survival can be demonstrated either by a contingency chi(2) type of analysis or regression analysis. On the basis of the regression data, the minimal gametic doubling dose of radiation of this type for mutations resulting in death during (on the average) the first 17 years of life among liveborn infants conceived 0-13 years after parental exposure is estimated at 46 rem for fathers and 125 rem for mothers. On the basis of experimental data, the gametic doubling dose for chronic, low-level radiation would be expected to be three to four times this value for males and as much as 1000 rem for females.     

Cell cycle delay in murine pre-osteoblasts is more pronounced after exposure to high-LET compared to low-LET radiation

Space radiation contains a complex mixture of particles comprised primarily of protons and high-energy heavy ions. Radiation risk is considered one of the major health risks for astronauts who embark on both orbital and interplanetary space missions. Ionizing radiation dose-dependently kills cells, damages genetic material, and disturbs cell differentiation and function. The immediate response to ionizing radiation-induced DNA damage is stimulation of DNA repair machinery and activation of cell cycle regulatory checkpoints. To date, little is known about cell cycle regulation after exposure to space-relevant radiation, especially regarding bone-forming osteoblasts. Here, we assessed cell cycle regulation in the osteoblastic cell line OCT-1 after exposure to various types of space-relevant radiation. The relative biological effectiveness (RBE) of ionizing radiation was investigated regarding the biological endpoint of cellular survival ability. Cell cycle progression was examined following radiation exposure resulting in different RBE values calculated for a cellular survival level of 1 %. Our findings indicate that radiation with a linear energy transfer (LET) of 150 keV/μm was most effective in inducing reproductive cell killing by causing cell cycle arrest. Expression analyses indicated that cells exposed to ionizing radiation exhibited significantly up-regulated p21(CDKN1A) gene expression. In conclusion, our findings suggest that cell cycle regulation is more sensitive to high-LET radiation than cell survival, which is not solely regulated through elevated CDKN1A expression.     

Power saturation of ESR signal in ammonium tartrate exposed to 60Co gamma-ray photons, electrons and protons

In this paper we present an investigation of the electron spin resonance (ESR) line shape of ammonium tartrate (AT) dosimeters exposed to radiation with different linear energy transfer (LET). We exposed our dosimeters to gamma-ray photons ((60)Co), 7 MeV and 14 MeV initial energy electrons, and 19.3 MeV initial energy protons. The differences in the power saturation behavior of ESR spectra of AT irradiated with photons, electrons and protons could be correlated to the effective LET of the radiation beams. We analyzed the behavior of peak-to-peak amplitude as a function of microwave power, and we developed a fitting procedure that permits us to obtain the dependence of the homogeneity parameter of the line shape on the LET of the radiation using the Castner saturation theory. This simple procedure allows us to distinguish the LET of the radiation beam.     

Mortality in the offspring of individuals living along the radioactively contaminated Techa River: a descriptive analysis

From 1949 onwards, radioactive waste was released into the Techa River in the southern Urals and the population living along the river was exposed to ionising radiation. Relocation of these people did not start until several years later, causing many individuals to be exposed to substantial doses from internal and external radiation. The identification and follow-up of the exposed individuals started more than 40 years ago and is still continuing. The Techa River offspring cohort (TROC) that has recently been established, comprises 10,459 children born to at least one parent living along the Techa River during the period 1950-1992. Of these children, 3,897 were born during the period of highest release, i.e. between 1950 and 1956 and might thus have been exposed in utero. A total of 1,103 individuals have since died mainly due to infectious and respiratory diseases, injury and poisoning. Only 25 cases were identified as having died of a malignant condition. The radioactive contamination of the Techa River in the southern Urals gives a unique possibility to study the adverse effects of protracted exposure to ionising radiation in a large well-described cohort. The Techa River offspring cohort will make it possible to study the effects on those exposed in utero or early in life and the follow-up of the cohort in the future is, therefore, of great importance. Comparisons with other cohorts of humans exposed early in life, will increase our knowledge in this field of research.     

Mortality associated with HIV-1 infection over five years in a rural Ugandan population: cohort study.

OBJECTIVE: To assess the impact of HIV-1 infection on mortality over five years in a rural Ugandan population. DESIGN: Longitudinal cohort study followed up annually by a house to house census and medical survey. SETTING: Rural population in south west Uganda. SUBJECTS: About 10,000 people from 15 villages who were enrolled in 1989-90 or later. MAIN OUTCOME MEASURES: Number of deaths from all causes, death rates, mortality fraction attributable to HIV-1 infection. RESULTS: Of 9777 people resident in the study area in 1989-90, 8833 (90%) had an unambiguous result on testing for HIV-1 antibody; throughout the period of follow up adult seroprevalence was about 8%. During 35,083 person years of follow up, 459 deaths occurred, 273 in seronegative subjects and 186 in seropositive subjects, corresponding to standardised death rates of 8.1 and 129.3 per 1000 person years. Standardised death rates for adults were 10.4 (95% confidence interval 9.0 to 11.8) and 114.0 (93.2 to 134.8) per 1000 person years respectively. The mortality fraction attributable to HIV-1 infection was 41% for adults and was in excess of 70% for men aged 25-44 and women aged 20-44 years. Median survival from time of enrollment was less than three years in subjects aged 55 years or more who were infected with HIV-1. Life expectancy from birth in the total population resident at any time was estimated to be 42.5 years (41.4 years in men; 43.5 years in women), which compares with 58.3 years (56.5 years in men; 60.5 years in women) in people known to be seronegative. CONCLUSIONS: These data confirm that in a rural African population HIV-1 infection is associated with high death rates and a substantial reduction in life expectancy.     

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.     

Life shortening in mice exposed to fission neutrons and gamma rays. IV. Further studies with fractionated neutron exposures

When mice were exposed to a total dose of 240 rad of fission neutrons divided into two, four, or six fractions given at 1-week intervals, more life shortening was observed than was seen after a single exposure. Maximum life shortening was observed with four fractions, although the value for six fractions was not significantly lower. Much of the augmentation effect was attributable to an increase in early deaths during the first 200-300 days after exposure, although differences persisted throughout the lifetime of the animals. The changes in life shortening were associated with changes in the distribution of causes of death; however, decrementation of the populations for any given specific cause of death failed to eliminate completely the differences in mean aftersurvival time.     

Lenticular opacities in populations exposed to chronic low-dose-rate gamma radiation from radiocontaminated buildings in Taiwan.

Chen, W-L., Hwang, J-S., Hu, T-H., Chen, M-S. and Chang, W. P. Lenticular Opacities in Populations Exposed to Chronic Low-Dose-Rate Gamma Radiation from Radiocontaminated Buildings in Taiwan. Radiat. Res. 156, 71-77 (2001).Epidemiological and experimental studies have revealed the cataractogenic potential of large acute doses of radiation. However, studies on the dose-response effect and the incidence of lenticular changes after exposure to chronic low doses of radiation have seldom been conducted. To evaluate quantitatively the lenticular changes in a population exposed to chronic low-dose-rate gamma radiation in their daily living or school environment in steel buildings contaminated with (60)Co in Taiwan, a total of 114 exposed individuals participated in a thorough ophthalmological examination in 1998. The lenticular opacities were evaluated by slit-lamp biomicroscopy after full pupil dilatation and were scored by the Lens Opacities Classification System III (LOCS III) and a modified subclinical minor lenticular focal defects system. These individuals were further divided into those less than 20 years old, those between 20 and 40 years old, and those more than 40 years old to evaluate the effects of age. The cumulative doses were assessed for each individual using the Taiwan Cumulative Dose (TCD) estimation system. A significant dose-dependent increase in the numbers of focal lens defects in those less than 20 years old was demonstrated, while less significant changes were observed in the other two age groups or by the LOCS III scoring. Results suggested that chronic low-dose-rate irradiation might induce minor lenticular changes, especially in lenses of young subjects. The delayed clinical changes in these young exposed subjects warrants further long-term follow-up.     

A systematic review on the effect of low-dose radiation on hearing

Numerous studies have documented the adverse effects of high-dose radiation on hearing in patients. On the other hand, radiographers are exposed to a low dose of ionizing radiation, and the effect of a low dose of radiation on hearing is quite abstruse. Therefore, the present systematic review aimed to elucidate the effect of low-dose ionizing radiation on hearing. Two authors independently carried out a comprehensive data search in three electronic databases, including PUBMED/MEDLINE, CINAHL, and SCOPUS. Eligible articles were independently assessed for quality by two authors. Cochrane Risk of Bias tool was used assess quality of the included studies. Two articles met the low-dose radiation exposure criteria given by Atomic Energy Regulatory Board (AERB) and National Council on Radiation Protection (NCRP) guidelines. Both studies observed the behavioral symptoms, pure-tone hearing sensitivity at the standard, extended high frequencies, and the middle ear functioning in low-dose radiation-exposed individuals and compared with age and gender-matched controls. One study assessed the cochlear function using transient-evoked otoacoustic emissions (TEOAE). Both studies reported that behavioral symptoms of auditory dysfunction and hearing thresholds at extended high frequencies were higher in radiation-exposed individuals than in the controls. The current systematic review concludes that the low-dose ionizing radiation may affect the hearing adversely. Nevertheless, further studies with robust research design are required to explicate the cause and effect relationship between the occupational low-dose ionizing radiation exposure and hearing.

     

Effects of exposure of newborn patched1 heterozygous mice to GSM, 900 MHz

Patched1 heterozygous knockout mice (Ptc1+/-), an animal model of multiorgan tumorigenesis in which ionizing radiation dramatically accelerates tumor development, were used to study the potential tumorigenic effects of electromagnetic fields (EMFs) on neonatal mice. Two hundred Ptc1+/- mice and their wild-type siblings were enrolled in this study. Newborn mice were exposed to 900 MHz radiofrequency radiation (average SAR: 0.4 W/kg for 5 days, 0.5 h twice a day) or were sham exposed. We found that RF EMFs simulating the Global System for Mobile Communications (GSM) did not affect the survival of the mice, because no statistically significant differences in survival were found between exposed and sham-exposed animals. Also, no effects attributable to radiofrequency radiation were observed on the incidence and histology of Ptc1-associated cerebellar tumors. Moreover, the skin phenotype was analyzed to look for proliferative effects of RF EMFs on the epidermal basal layer and for acceleration of preneoplastic lesions typical of the basal cell carcinoma phenotype of this model. We found no evidence of proliferative or promotional effects in the skin from neonatal exposure to radiofrequency radiation. Furthermore, no difference in Ptc1-associated rhabdomyosarcomas was detected between sham-exposed and exposed mice. Thus, under the experimental conditions tested, there was no evidence of life shortening or tumorigenic effects of neonatal exposure to GSM RF radiation in a highly tumor-susceptible mouse model.     

Radiation Hazards Control in Survival Operations in the Event of a Nuclear War

The concepts of radiation protection in survival operations are explained, and procedures devised to control radiation hazards for the protection of the population and maintenance of the operating efficiency of survival operations personnel are presented.Radiation protection is a command function. The medical responsibility is to provide advice on the probable effects of radiation exposure in the light of existing knowledge of these effects in man.The major hazard is that of external exposure to penetrating gamma radiation. Radiation exposure guides indicate that persons may be exposed to not more than 100 r whole body radiation in a six-week period, or 200 r whole body radiation in a period in excess of six weeks, without loss of operational efficiency. Beta radiation from fallout deposited on skin or clothing may produce burns, but these injuries will not be incapacitating and can be controlled by simple procedures.The internal hazard is mainly from ingestion of food or water contaminated with radioactive material. For protection, only canned or packaged foods and water from covered or deep wells are consumed during the early days after a nuclear attack.