Age-dependent effects on radiation-induced carcinogenesis in the rat thyroid.

Childhood radiation exposure is a known thyroid cancer risk factor. This study evaluated the effects of age on radiation-induced thyroid carcinogenesis in rats irradiated with 8 Gy X-rays. We analyzed cell proliferation, cell death, DNA damage response, and autophagy-related markers in 4-week-old (4W) and 7-month-old (7M) rats and the incidence of thyroid tumors in 4W, 4-month-old (4M), and 7M rats 18 months after irradiation. Cell death and DNA damage response were increased in 4W rats compared to those in controls at 1 month post-irradiation. More Ki-67-positive cells were observed in 4W rats at 12 months post-irradiation. Thyroid tumors were confirmed in 61.9% (13/21), 63.6% (7/11), and 33.3% (2/6) of irradiated 4W, 4M, and 7M rats, respectively, compared to 0%, 14.3% (1/7), and 16.7% (1/6) in the respective nonirradiated controls. There were 29, 9, and 2 tumors in irradiated 4W, 4M, and 7M rats, respectively. The expression of several autophagy components was downregulated in the area surrounding radiation-induced thyroid carcinomas in 4W and 7M rats. LC3 and p62 expression levels decreased in radiation-induced follicular carcinoma in 4W rats. Radiosensitive cells causing thyroid tumors may be more prevalent in young rats, and abrogation of autophagy may be associated with radiation-induced thyroid carcinogenesis.

Impact of mouse strain and sex when modeling radiation necrosis.

BACKGROUND: Murine models are among the most common type of preclinical animal models used to study the human condition, but a wide selection of different mice is currently in use with these differences potentially compromising study results and impairing the ability to reconcile interstudy results. Our goal was to determine how the strain and sex of the mice selection would affect the development of radiation necrosis in our murine model of radiation-induced cerebral necrosis. METHODS: We generated this model by using a preclinical irradiator to irradiate a sub-hemispheric portion of the brain of mice with single-fraction doses of 80 Gy. Eight possible combinations of mice made up of two different with two substrains each (BALB/cN, BALB/cJ, C57BL/6 N, and C57BL/6 J) and both sexes were irradiated in this study. Radiation necrosis development was tracked up to 8 weeks with a 7 T Bruker MRI utilizing T2-weighted and post-contrast T1-weighted imaging. MRI results were compared to and validated with the use of histology which utilized a scale from 0 to 3 in ascending order of damage. RESULTS: Both time post-irradiation and strain (BALB/c vs C57BL/6) were significant factors affecting radiation necrosis development. Sex was in general not a statistically significant parameter in terms of radiation necrosis development. CONCLUSION: Mouse strain thus needs to be considered when evaluating the results of necrosis models. However, sex does not appear to be a variable needing major consideration.

Non-neoplastic and neoplastic thyroid disease in beagles irradiated during prenatal and postnatal development.

To evaluate the lifetime hazards of exposure to ionizing radiation, 1,680 beagles received whole-body exposures to 60Co gamma rays or sham exposures during development. Eight groups of 120 dogs each received mean doses of 16-18 or 81-88 cGy at 8, 28 or 55 days of gestation, or at 2 days after birth. One group of 120 dogs received a mean of 83 cGy at 70 days of age and one group of 240 dogs received a mean of 81 cGy at 365 days of age. Sham irradiations were given to 360 controls. Sexes were equally represented. In 1,343 dogs allowed to live out their life span, heritable lymphocytic thyroiditis with hypothyroidism was a major contributor to mortality. Irradiated dogs had a decreased risk for hypothyroidism, a finding that was surprising and not easily explained. Of the 1,343 life-span dogs, those exposed as neonates at 2 days of age or as juveniles at 70 days of age had evidence for an increased risk for thyroid follicular cell neoplasia. Hypothyroid dogs had a significantly increased risk for thyroid neoplasia, including greater risk for carcinomas, but no evidence of a greater sensitivity to radiation-induced tumors. In dogs with normal thyroid function irradiated at 2 or 70 days of age there was increased risk for benign and malignant follicular cell neoplasms, including multiple neoplasms. No difference between sexes was noted. These findings related to age sensitivity in the dog were consistent with the high risk for radiogenic thyroid neoplasia in humans after exposure during early childhood.

Timing of concomitant boost irradiation affects incidence and severity of intestinal complications.

PURPOSE: In an effort to increase the therapeutic ratio of radiation therapy, so-called "nonstandard" irradiation regimens are being used more frequently. One such regimen, concomitant boost, entails giving a second daily fraction during part of the treatment course, thus reducing the total treatment time and decreasing the opportunity for tumor cell proliferation during treatment. The probability of tumor control is, therefore, increased for a given total dose. Timing of the boost, i.e., whether it is given early or late during the treatment course, affects both normal tissue and tumor response. This study assessed the influence of timing of a second daily boost on the development of intestinal radiation injury in a rat model. METHODS AND MATERIALS: A functionally intact segment of distal ileum was sutured to the inside of the scrotum in 52 orchiectomized, male Sprague-Dawley rats. After a 3-week postoperative recovery period, the intestine contained in the "scrotal hernia" was irradiated. All rats received a total dose of 50.4 Gy, given over a 12-day period as two different boost regimens, daily fractions of 2.8 Gy plus six concomitant boost doses of 2.8 Gy. The early boost group received the additional boost during the first 6 days and the late boost group received the additional boost during the last 6 days. The boost was given 6 h after the daily fraction. Groups of rats were sacrificed at 24 h (acute changes), 2 weeks (subacute changes), and 26 weeks (chronic changes) after the end of the irradiation schedule. Radiation injury was assessed by frequency of radiation-induced complications, histopathologic radiation injury score, collagen content, and epithelial cytokinetics. RESULTS: Radiation injury in the early boost group was significantly more severe than in the late boost group in terms of incidence of complication and histopathologic injury. Relative collagen content of irradiated intestine was significantly increased in the early boost group when compared to the late boost group at 2 weeks and at 26 weeks. Irradiated intestine in the early boost group exhibited decreased labeling index at 2 weeks, whereas irradiated intestine in the late boost group exhibited normal labeling index and increased total crypt cellularity at 2 weeks. CONCLUSION: When small intestine has to be included in the treatment field during radiation therapy, concomitant boost should be given towards the end of the radiation schedule, after the onset of compensatory proliferation, to minimized the risk of subsequent complications.

The concentration of light in the human lens.

PURPOSE: This thesis explores the idea that light energy, especially ultraviolet light, contributes to the unequal distribution of cataract around the world and to the development of cortical opacities. METHODS: In the first section, the thesis reviews historical concepts of the function of the lens and the nature of cataract, epidemiologic data on the global distribution of cataract, and clinical observations of the predominant location of cortical opacification. Second, computer ray tracings and geometric optics demonstrate the passage of light of varying angle of incidence within the lens. Third, two models of the human eye are used to study the refraction of light by the cornea and lens and illustrate the concentration of energy at the equatorial plane of the lens. RESULTS: Cataract prevalence increases with proximity to the earth's equator, and cortical cataract is most common in the inferior and inferonasal lens. Theoretical studies and the eye models both demonstrate that the concentration of light within the lens increases with angle of incidence, and the eye models suggest that the inferior and inferonasal lens receives significantly more energy than other sections of the lens. CONCLUSION: The prevalence of cataract and exposure to ultraviolet energy both increase with decreasing latitude. The most common location of cortical cataract in the inferonasal lens is consistent with the greater dose of light energy received by this portion of the lens. These studies suggest that the global distribution of cataract and the development of cortical cataract are at least in part dependent on the dose of ultraviolet light received by the lens.

Damage and morbidity from pneumonitis after irradiation of partial volumes of mouse lung.

PURPOSE: The aims of this study were to: (a) define the relationship of dose and volume irradiated to damage and morbidity in mouse lung, (b) determine the threshold volume for morbidity after partial lung irradiation; and (c) determine whether the response to radiation of mouse lung is independent of the region irradiated. METHODS AND MATERIALS: C3Hf/Kam female mice were used in this study. The fractional volume of the lung to be irradiated was determined by two methods, weights and computed tomography (CT) scanning. Two experiments were performed to define the volume effect and to determine whether the response of the mouse lung to radiation was homogeneous. In the first experiment, single doses of x-rays ranging from 12 to 20 Gy were given to partial volumes of 84%, 70%, and 40% including the base, 50%, 33%, and 17% including the apex, to 43% in the middle, and to the sum of 57% as 17% in the apex and 40% in the base. In the second experiment, the same volumes of 50% and 70-75% in the apex and base of the lung were irradiated with single doses ranging from 12-19.25 Gy. Morbidity from radiation pneumonitis was quantitated by two end points, breathing rate and lethality between 12 and 32 weeks after irradiation. Damage was assessed by histopathological evidence of pneumonitis. RESULTS: Clear well-defined dose-response curves were obtained for both breathing rate and lethality after all volumes irradiated. There was a clear volume-dependent shift of the dose-response curves for breathing rate and lethality at 28 weeks after irradiation, the end of the pneumonitis phase of damage, to higher doses compared with these data after whole-lung irradiation. In addition, the slopes of the dose-response curves for irradiation of partial lung volumes were more shallow compared to those after whole-lung irradiation. Increases in breathing rate correlated with lethality when the volume irradiated was equal to or greater than 50% of the reference volume. However, after irradiation of volumes smaller than 40%, breathing rate increases were not accompanied by death. A heterogeneous response of the mouse lung to radiation was observed in the first experiment and confirmed by the second experiment. For a given volume irradiated, the isoeffect dose was always less for the base than for the apex of the lung. The threshold volume for breathing rate changes was less than 17 and 40% when the irradiated volumes involved the apex and base, respectively. For lethality, the threshold volume was between 40 and 70% for the base and greater than 50% for the apex of the lung. Finally, damage as assessed by histological evidence of pneumonitis was observed in the irradiated area only. CONCLUSIONS: (a) The volume effect was resolvable in mice, (b) the volume effect in mouse lung exhibits a clear threshold for morbidity, (c) the threshold volume for morbidity is dependent on the end point, (d) the response of mouse lung is heterogeneous, dependent on the site irradiated, and is always greater for the same volumes irradiated in the base than the apex, and, (e) histopathological damage does not always produce observable morbidity.

Methods to prevent colonic injury in pelvic radiation.

PURPOSE: Radiation has become an adjunct in the treatment of pelvic malignancies. Attempts to prevent adjacent tissue injury have met with varying degrees of success, and the purpose of this study was to investigate potential radioprotective effects of an elemental diet, sodium meclofenamate, and vitamin A in an animal model of acute and chronic pelvic radiation previously described. METHODS: Female Sprague-Dawley rats, 200-250 grams, were anesthetized and then received 900 rads of pelvic radiation once per week for five weeks for a total of 4500 rads. Animals were divided into five groups. Treatment groups received radiation and elemental diet, radiation and vitamin A, radiation and sodium meclofenamate. Control animals received anesthesia only and no radiation. Vitamin A was given as a supplement to (662 IU/kg) standard rat chow. Elemental diet was given as a commercially available formula, whereas sodium meclofenamate was given as a postoperative supplement (5 mg/kg/day). All animals were given these treatments during the course of radiation therapy only. Histology of distal colon was measured at one week, five weeks, six months, and one year postradiation therapy. The distal two cm of colon were removed at necropsy and fixed in 10 percent formalin at each of the above time points. Histologic grade was determined by a previously described grading scale. RESULTS: Results showed a qualitative radiation injury that could be documented at one and five weeks postradiation. Elemental diet, vitamin A, and sodium meclofenamate prevented histologic changes that occurred at these time points. No difference in histologic grade was seen between any groups at six months and one year postradiation therapy. CONCLUSION: In summary, our model of pelvic radiation produces a definable radiation injury within the colon at one and five weeks postradiation. Use of elemental diet, vitamin A, and sodium meclofenamate prevented these changes.

[The use of the multivariate estimation method for the objective evaluation of the effect of antihypoxic therapy in the first 24 hours after an absolutely lethal radiation injury]. / Primenenie metoda mnogomernogo otsenivaniia dlia ob''ektivizatsii vliianiia antigipoksicheskoi terapii v pervye sutki posle absoliutno letal'nogo luchevogo porazheniia.

Three groups of rats (intact, irradiated with 30 Gy of gamma rays and treated after irradiation with the use of pharmacological and metabolic drugs protecting brain against hypoxia were studied. In 24 hours after the influence the animals have undergone the neurobehavioral testing and then were sacrificed, a number of neurochemical parameters depicting energy metabolism and metabolic GABA bypath in brain were studied (general number of parameters were 24). Using classical method of t-statistics only enhancement of labelled GABA catabolism and deterioration of general behavioral activity were verified, the modifying effect of the pharmacological and metabolic protection against hypoxia was not found. Using methods of multidimensional evaluation the protective and sanogenic character of the used method of therapy was verified. Thus, using discrimination analysis (Mahalanobis criterion) high similarity of intact and treated groups of animals was estimated. It was confirmed using methods of coupled and multiple correlation and method of route coefficients. The statistical connections between neurochemical and neurobehavioral parameters were found which can be useful for understanding of the mechanisms of the early postradiation syndrome development.

[Effect of low intensity and ultra high frequency electromagnetic irradiation on memory functions]. / Deistvie nizkointensivnogo élektromagnitnogo izlucheniia sverkhvysokoi chastoty na mnesticheskie funktsii.

The experiments on rats proved that low intensity electromagnetic waves result in retrograde amnesia due to benzodiazepine, gamma-aminobutyric acid and cholinergic mechanisms. Nootropic drug pyracethamum was proved to reduce the pathologic effect.

[Genetic effect of incorporated 137 Cs in male mice after single injection of the isotope]. / Geneticheskii éffect inkorporirovannogo 137 Cs u samtsov myshei pri odnokratnom vvedenii izotopa.

A comparative study of the incidence of genetic damages induced in mouse male germ cells by a single injection of 137Cs and external gamma-irradiation shows that the incidence of dominant lethal mutations in the postmeiotic cells is similar with both radiation types. The frequency of reciprocal translocations in stem cell spermatogonia was considerably lower with 137Cs than with external gamma-irradiation which might be attributed to the prolonged effect of the radionuclide.

[Genetic effect of incorporated 137 Cs on male mice after long-term administration of the isotope]. / Geneticheskii éffect inkorporirovannogo 137 Cs u samtsov myshei pri dlitelnom vvedenii izotopa.

A comparative study has been made of the incidence of genetic damages to male mouse germ cells induced by chronic action of incorporated 137Cs and external gamma-radiation. It has been shown that the genetic efficiency was nearly the same with both radiation types under conditions of equal, with respect to time and value, absorbed dose formation in gonads.

[An experimental assessment of the genetic effects of low doses of internal irradiation]. / Eksperimental'naia otsenka geneticheskikh éffektov malykh doz vnutrennego oblucheniia.

Genetic study of rats showed the possibility of registration of the minor doses of the inside and outside irradiation. The postmiosis mutations, number of reciprocal translocations in spermatogonia may be used for indexation of the effects.

Ultraviolet radiation, solar dermatosis, and cutaneous neoplasia in beagle dogs.

Beagle dogs that were part of a life span study of the effects of low-level ionizing radiation during development were evaluated for the incidence of skin neoplasia and solar dermatosis. A total of 991 dogs up to 14 years of age were examined. The dogs were housed in gravel-based, outdoor pens with doghouses in a high-altitude, high-sunshine level environment. Solar dermatosis was restricted to the sparsely haired, nonpigmented abdominal skin. Skin neoplasms were either removed surgically or found at necropsy. Solar dermatosis was diagnosed in 363 of the 991 dogs, an incidence of 36.6%. There were 175 hemangiomas, hemangiosarcomas, or squamous cell carcinomas of the skin in the 991 dogs. Of these, 129 tumors occurred in dogs with, and only 46 in dogs without, solar dermatosis. Of the dogs with solar dermatosis, 93 (26%) had at least one of the three tumor types, compared to only 44 (7%) of dogs without solar dermatosis. Thirty-two dogs had multiple tumor types and solar dermatosis, compared to only two dogs with multiple tumor types and no solar dermatosis. There was a highly significant correlation (P less than 0.001) between the occurrence of these tumor types and solar dermatosis in the unpigmented abdominal skin. This correlation was strongest for the malignant neoplasms. Whole-body gamma-radiation exposures were delivered at one of three prenatal or three postnatal ages up to 1 year of age. There appeared to be an increased risk for hemangiosarcomas and squamous cell carcinomas in dogs with solar dermatosis and given gamma-ray exposures at 1 year of age. This suggests an interaction between exposures to ionizing and ultraviolet radiation.

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.

[The effective dosage as the stimulating exposure in fractionated gamma irradiation]. / Effektivnaia doza kak razdrazhaiushchee vozdeistvie pri fraktsionirovannom gamma-obluchenii.

The study of early neurological disturbances (END) in rats after fractionated gamma irradiation with doses of 37.5-225 Gy at dose rate of 30.11 Gy/min has demonstrated that the initial response of animals to pulse ionizing radiation is a function of the electric charge induced by ionizing radiation. A change in the probability of occurrence of each of the END symptoms, with the increased intervals between exposures, is merely an indirect indication of the eliminating mechanisms and is intricately connected with the irritating charge value. The period of dose half-elimination in 16 min. The threshold effective dose rate leading to END is of the order of 2.12 Gy/min. The proposed empiric relationships permit to correlate the probability of END symptom occurrence with the continuous quantitative parameter of fractionated irradiation, that is, with an effective dose as an analogue of the irritating effect.

Future development of biological understanding of radiation protection: implications of nonstochastic effects.

Radiation-protection standards are based on minimizing or preventing biological effects in exposed populations. Radiation-induced biological effects can be classified as stochastic--malignant and hereditary diseases for which the probability of an effect occurring is a function of dose without threshold--and nonstochastic--inflammatory and degenerative diseases for which the severity and frequency of the effect varies with the dose and for which a threshold is present. The current International Commission on Radiation Protection (ICRP) approach for setting limits for intakes of radionuclides by workers, which accounts for doses to significantly exposed organs of the body, is based on limitation of stochastic effects in most situations. When setting exposure limits, nonstochastic effects are generally considered to be unlikely at the limits for stochastic effects. In some situations, limits based on prevention of nonstochastic effects are lower than for stochastic effects. This review considers the threshold radiation doses for thyroid, bone, liver and lung and their relationship to the limits recommended by the ICRP and the cancer risks at the limits. This review indicates that the threshold dose for nonstochastic effects in thyroid and lung is much above the dose limit as advocated by ICRP. The threshold dose for nonstochastic effects in bone and liver is much closer to the dose limit, but protection from nonstochastic effects should still be afforded by the dose limits.

[Assessment of the genetic risk of radiation by irradiation data from laboratory mammals]. / Otsenka geneticheskogo riska radiatsii po dannym oblucheniia u laboratornykh mlekopitaiushchikh.

An attempt has been made to assess quantitatively genetic risk of radiation for man based on mammalian (mostly mouse) data and using the direct method proposed by UNSCEAR. The parameter employed was induction of reciprocal translocations. Two assumptions were made: human radiosensitivity equals that of the mouse; and dose-response is linear. From observations with acute gamma irradiation the estimate of risk per 10(-2) Gy was as follows: 39 translocation heterozygotes are expected among one million F1 conceptions, 5 cases of multiple congenital anomalies, 25 abortions recorded and 49 unrecorded. Chronic gamma irradiation at dose rates of 1.3 X 10(-5), 1.7 X 10(-4) and 1.0 X 10(-4) Gy/min was 3 to 10 times less effective. Exposure to 4.2 GeV deuterons proved inferior in effectiveness to gamma irradiation. Chronic exposure to 4.1 MeV neutrons delivered at 8 X 10(-4) Gy/min showed 7 times the effectiveness of chronic gamma irradiation. Administration of tritiated water (from 37 to 37 X 10(2) kBq/g b.w.) to rats entailed a risk of the same order of magnitude as external chronic gamma irradiation. Reduction of genetic risk was achieved by pretreatment with either AFT-, ATP-serotonin mixtures or the molecular combinations, Adeturon and Cytriphos. Study of interspecies differences in genetic radiosensitivity showed decline in the following order: rat-rabbit-mouse-Syrian hamster. A dose-rate effect was most clearly seen in the rat, and least clearly in the rabbit. In female mice, examination of oocyte depletion indicated primary follicles to be highly susceptible to acute gamma irradiation; decrease in sensitivity was observed beginning with stage 4. Chronic gamma irradiation was found to be less effective.

[Combined, local and chemical protection of the body against radiation exposure during space flight]. / Kombinirovannaia, lokal'naia i khimicheskaia zashchita organizma ot radiatsionnogo vozdeistviia pri kosmicheskikh poletakh.

This paper summarizes studies of the combined protection of dogs exposed to acute high energy proton irradiation at a dose of 400 rad. The chemical radioprotector--mexamine--was injected intramuscularly at a dose of 10 mg/kg or administered per os at a dose of 75 mg/kg. During the exposure 14.5% of bone marrow was shielded. The dose behind the shielding was 250 rad. The combined use of mexamine administered per os and partial bone marrow shielding provided better protection, whereas either type of protection applied separately proved inefficient.

[Patterns in the development of radiation tumors of the stomach and intestines]. / Nekotorye zakonomernosti razvitiia luchevykh opukholei zheludka i kishechnika.

In the experiments on dogs and rats it was shown that gastric and intestinal neoplasms arise under the influence of different kinds of radiation, these may be located in all portions of the stomach and bowel and are of a different histological origin. They are not infrequently primary multiple, mostly benign neoplasms which show multicentric growth. The frequency of tumors appearance, their localization, an average latent period, the degree of malignancy and multiplicity are conditioned by the amount of tissue dosage, the topography of their distribution in the alimentary tract and the level of total irradiation of the organism. With the increased dosage of local irradiation the latent period and multiplicity are decreased, while the incidence of malignancy raised. The optimum levels of the tissue dosage and the time of maximum tumor appearance were determined for each type of radiation.