The initiating potential of a range of 4 MeV X-rays was studied using the mouse skin two-stage model of carcinogenesis. A single dose of radiation was followed by promotion with 12-O-tetradecanoyl phorbol-13-acetate (TPA). The effect of TPA on tumor incidence when applied as a single dose 24 hours prior to irradiation was examined. Studies were also designed to investigate the effect of promotion duration on tumor incidence. Animals were promoted with TPA for 10 or 60 weeks. Evidence presented here indicates that ionizing radiation can act as an initiator in this model system. All animals that were promoted with TPA for the same duration had a similar incidence of papillomas (pap) regardless of radiation or TPA pretreatment. However, squamous cell carcinomas (scc) arose only in animals that were initiated with ionizing radiation followed by TPA promotion. Increasing the promotion duration enhanced the incidence of scc at the lower initiation dose. TPA pretreatment at the higher irradiation dose resulted in an overall decrease in tumor incidence. At the lower dose of radiation, TPA pretreatment resulted in an increase in the incidence of scc. The incidence of basal cell carcinomas (bcc) was dose dependent and appeared to be independent of TPA promotion. Although ionizing radiation acts as a weak initiator in mouse skin, the conversion of pap to scc was higher than that reported for chemical initiators. To test this further animals were initiated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) followed by biweekly promotion with TPA. After 20 weeks of promotion, the animals were treated with either acetone, TPA or 8 fractions of 1 MeV electrons. Data indicate that the dose and fractionation protocol used in this study enhanced the progression of pre-existing pap. To examine the role of oncogene activation in radiation induced mouse skin tumors, DNA from various tumors (pap, bcc, scc) were examined for the presence of dominant transforming activity by the NIH3T3 and Rat-2 focus assays. Dominant transforming activity was observed in all tumor types but not in normal or treated epidermis or corresponding liver. The transformed phenotype was further confirmed by growth in soft agar and tumorigenicity in Nude mice. Southern blot hybridization to ras (Ha, Ki, N), raf, neu, erbB and β-lym indicate that these genes are not responsible for the observed transforming activity. These data suggest that the oncogenic sequences activated in these tumors are unique. The work presented here also provides evidence for novel c-myc transcripts and corresponding genomic rearrangements in a few of the tumors studied.

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The irradiation of cells in culture is an essential part of many radiation biology experiments. Since these experiments necessarily involve the irradiation of cell culture vessels and nutrient medium, the possibility of effects due to the interactions of irradiated material with growing cells needed to be investigated. In the present study the micronucleus frequency in Chinese hamster ovary (CHO) cells as a function of such parameters as type of radiation, type of cell substrate, changes in cell environment, and time course of the effect were characterized. Observations of the persistence of micronucleus formation in irradiated CHO cells reveal that the number of cells containing micronuclei reaches its maximum within nine hours after irradiation and remain elevated for at least five days. The influence of the cell environment on micronucleus formation in CHO cells was examined by plating cells in preirradiated nutrient medium or on preirradiated cell culture vessels. In all experiments, pre-irradiation of the cell substrate (the culture dish or culture dish filled with medium) led to a significantly higher micronucleus frequency than when cells were plated on un-irradiated substrate. The difference is most pronounced at the lowest doses examined. These results suggest that methods of cell culture vessel sterilization and the composition of cell attachment surfaces could be confounding factors, particularly in the experiments which are intended to examine the response of cells exposed to low doses of ionizing radiation.

Thesis (M. Sc.)--University of Canterbury, 2009. / Typescript (photocopy). Includes bibliographical references (leaves 57-63). Also available via the World Wide Web.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1982. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 159-165).

During the last two decades there has been growing interest in the application of organic dielectric liquids for dosimetry of ionizing radiations. The main problem associated with the liquid application in radiation detectors has been the difficulty in securing saturation charge collection and controlled charge multiplication to permit operation in the ionization chamber and proportional counter modes. In an attempt to understand better the fundamental mechanisms involved in the limitation to charge collection an extensive review has been made of the published theoretical and experimental research. The theoretical work attributes the unattainability of saturation charge collection to losses caused by different types of recombination depending on the initial separation of ions liberated and on the magnitude of the applied electric field. None of the presented theories is found to be fully consistent with the reported experimental results obtained for a range of different di-electric liquids, especially in high field regions. Liquid hydrocarbons, especially those characterised by high charge mobility and high yield of ions, have been widely investigated experimentally to explore the mechanisms responsible. The experimental measurements are found to be strongly dependent on: the purity of the liquids, their chemical structure, the type of materials used for the electrodes in contact with the liquid and on the temperature. These conclusions reflect inadequacies both in the theoretical knowledge of charge transport in liquids and in the practical difficulties of measurement which indicate the need for more detailed experimental investigation. The origin of the natural intrinsic dark current in liquids is found to be due to the presence of impurities; the effect of cosmic-ray interactions; and the presence of radioactivity in the construction materials of the detector. Upon application of high electric fields other factors such as electron emission, molecular dissociation and field ionization become significant. The extensive range of results reported on transport properties (mobility, free ion-yield, conduction band energy, di-electric strength, and theoretical W-values) of charge earners in liquid hydrocarbons and liquified rare-gases, and their dependence on the electric field and temperature have been compiled into tabulated form in appendix B to provide a ready reference. New experimental work, aimed at assessing the role and the key factors involved, was conducted with two separate ionization chambers filled with liquid tetramethylsilane (TMS). Information was obtained on the dependence of the current-field characteristic, for the dark and ionization currents, on various parameters such as purity, electrode separation, surface asperities, electrode construction material, and the charge collection area. For the ionization current, the dependence on the radiation intensity, produced with a 4 mCi source of 57Co of y-rays, was also measured. Liquid purity was confirmed to be very important. Chemical and electrical purification, could lead to orders of magnitude reduction in the background dark current. Tests, made to assess the efficiency of ion collection in liquid TMS, indicated the need for much larger, and more uniform, electric fields. These were achieved by fitting electrodes made from tissue-equivalent plastic. The improved surface smoothness of the latter was found to improve the current-to-noise ratio by a factor of 2-3 orders of magnitude. From the results of the present investigation at fields ? 500 kV/cm it was concluded that the saturation collection of charge was attainable. Limitation to achieving saturation is discussed in terms of charge multiplication produced inside localised gas bubbles on the electrode surfaces. Field induced polarization of liquid molecules could be a contributing factor at high fields. There appears to be realistic prospects of achieving saturation collection of charge, and possibly proportional multiplication, by appropriate design using advanced technology to ensure ultra-smooth surfaces and uniform electric fields.

This thesis describes a long-term study in which the genetic health of a population accidentally exposed to ionizing radiation of cesium-137. The Goiânia (Brazil) radiological accident of September 1987 involved 249 individuals exposed to doses up to 7 Gy, and included four fatalities. We have investigated the genetic effects of radiation exposure in this population using both cytogenetic and molecular endpoints in T-lymphocytes. The micronucleus assay differentiated between groups exposed to different levels of ionizing radiation. At the molecular level two methods were employed: (1) the hprt clonal assay; and (2) the determination of microsatellite instability. The hprt assay involves in vitro culturing of T-cells and the selection of 6-thioguanine-resistant hprt mutant clones which were then characterized at the molecular level using both RT-PCR and genomic analysis. Exposure to ionizing radiation initially elevated the mutation frequency but this effect gradually diminished, so that 4.5 years no significant increase was observed. This limitation makes the hprt T-cell assay unsuitable for the study of long term past exposure. Analysis of the spectrum of hprt mutations recovered from 10 individuals exposed to relatively high doses of ionizing radiation revealed a significant increase (3.8-fold) in the frequency of A:T → G:C mutations in the exposed group. This increase in A:T → G:C transitions is consistent with the effects of ionizing radiation in prokaryotes and lower eukaryotes and likely reflects the mispairing of radiation-induced thymine, glycol with guanine. In addition, a two-fold increase in the frequency of deletions not readily explained by slippage events and hence which may reflect ionizing radiation-induced DNA strand breakage was also observed. Microsatellite instability was also investigated. Fluorescent PCR and automated DNA sequencer analysis, using genomic DNA from mononuclear cells, were used to investigate the frequency of microsatellite alterations in exposed and non-exposed populations. We examined a total of 200 and 190 alleles respectively and found that the microsatellite instability distribution in the two groups were not different. Our assay lacked sufficient sensitivity to discriminate between spontaneous and induced microsatellite instability and it is, therefore, not suitable for population monitoring. Finally, despite the minimal database, we used the micronucleus and hprt mutant frequency data to estimate the risk associated with radiation exposure for the Goiânia population. The estimated genetic risk for the exposed group was approximately a 24-fold increase in dominant disorders in the first post-exposure generation. Moreover, the risk of carcinogenesis in this population was estimated to be increased by a factor in the range of 1.4 to 1.5 compared to the population at large. / Graduate

Most breast cancer patients undergo radiation diagnostics and are also treated with radiotherapy. In addition to being an important treatment modality, ionizing radiation (IR) is a potent tumour-causing agent that has been linked to breast cancer development. However, the exact molecular etiology of IR-induced mammary gland carcinogenesis remains unknown. We set out to analyze the role of DNA methylation in mammary gland responses to low dose IR using a well-established rat model. We also studied low dose IR effects on global gene expression and microRNAome. We found that exposure to low, mammography-like dose of IR led to a significant loss of global DNA methylation in rat mammary gland tissue. Furthermore, low dose IR significantly affected rat mammary gland transcriptome and microRNAome. The datasets generated within the scope of this thesis may be used to identify novel predictive biomarkers for assessment of the magnitude of IR effects on mammary gland tissue. / xi, 120 leaves ; 29 cm