Effects Of high-LET Radiation Research Articles

Cellular and molecular alterations in human epithelial cells transformed by high let radiation

An understanding of the radiobiological effects of high LET radiation is essential for human risk estimation and radiation protection. In the present study, we show that a single, 30 cGy dose of 150 keV/μm 4He ions can malignantly transform human papillomavirus immortalized human bronchial epithelial [BEP2D] cells. Transformed cells produce progressively growing tumors in nude mice. The transformation frequency by the single dose of alpha particles is estimated to be approximately 4 X10 −7. Based on the average cross-sectional area of BEP2D cells, it can be calculated that a mean traversal of 1.4 particles per cell is sufficient to induce tumorigenic conversion of these cells 3 to 4 months post-irradiation. Tumorigenic BEP2D cells overexpress mutated p53 tumor suppressor oncoproteins in addition to the cell cycle control gene cyclin D1 and D2. This model provides an opportunity to study the cellular and molecular changes at the various stages in radiation carcinogenesis involving human cells.

Mechanisms underlying cellular radiosensitivity and R.B.E.: Introductory remarks

A general outline of the symposium titled “Mechanisms underlying cellular radiosensitivity and R.B.E.” will be given in the introduction. The essential topics of molecular radiation biology are described with respect to the damage, repair and mutagenesis caused by high-LET irradiation to cellular DNA. The importance of clustered DNA lesions (locally multiply damaged sites) formed in vivo is discussed. This symposium is devoted to the mechanisms of the biological effects of radiation with high LET, especially with regard to the effects of heavy ions and neutrons which may cause possible risks in space flight, (e.g. carcinogenesis and mutagenesis). Detailed understanding of these risks, however, demands knowledge of the molecular mechanisms involved in the biological effects of high-LET radiations. Thus, it was the organizers' idea to hold a symposium dealing with primary physical and chemical events caused in cellular deoxyribonucleoproteins by densely-ionizing radiations and to relate them to track structures and energy transfer processes. The mechanisms of DNA damage were regarded from different points of view including those considering DNA repair and mutagenesis. Problems associated with cell survival and radiation protection were discussed as well. Our knowledge of the molecular mechanisms of high-LET radiation actions, however, is limited compared to what we know about low-LET radiation effects (e.g. from gamma-rays or X-rays). To emphasize this statement, I would like to summarize briefly the open questions in molecular radiation biology, what we know already about low-LET effects and what is lacking describing the effect of high-LET radiation.

An Integrated Model For Radiation Induced Cancer

Abstract Risk estimates for radiation induced cancer are based on epidemiological data, principally the Japanese A bomb survivors. These estimates for radiation are better known than for any other environmental pollutant, but they do not relate directly to exposure to low doses and low dose rates. Recent rapid advances in molecular genetics, coupled with steady gains in cellular biology, radiation physics and chemistry led to the notion that the time may not be far off when it may be possible to arrive at human cancer risk estimates entirely from laboratory data. Whether risk estimates based on laboratory data will ever replace estimates based on epidemiological studies is an open question. What is clear is that laboratory data can supplement the present risk estimates by providing information on the relative effectiveness of high LET radiations, the importance of dose rate and dose protraction, and by identifying subpopulations which are unusually sensitive or resistant to radiation carcinogenesis.

Effect of LET on chromosomal aberration yields. I. Do long-lived, exchange-prone double strand breaks play a role?

Dicentric chromosomal aberrations produced by ionizing radiation probably result from pairwise interaction of DNA double strand breaks (dsbs). It has been suggested that high LET radiation may preferentially produce a subclass of 'severe' dsbs that are long-lived and/or exchange-prone, and that it is the production of these severe dsbs which account for the increased biological effectiveness of high-LET radiation. We present a quantitative formalism to describe the induction of these severe dsbs, and the subsequent production of exchange-type chromosomal aberrations. Using a Markov model and microdosimetric methods, we conclude that dicentric production by such severe dsbs has properties similar to those observed at high LET. Specifically, at high doses, the yield is nearly linear with dose even if dsbs from different tracks interact. The model is applied to published data on dicentric aberrations produced by irradiation of human lymphocytes in vitro. Corrections for the effects of interphase death are estimated. From comparisons with the experiments we conclude that interaction of severe dsbs could make a significant contribution to the observed dicentric production at high LET and also perhaps for low doses (though not high doses) at low LET. Proximity explanations of high-LET effects continue to offer the main prospect for obtaining a unified picture of chromosomal aberration formation by all ionizing radiation types, but a hybrid model in which severe dsbs contribute to the high-LET aberration yield cannot be ruled out. If all or part of high-LET radiation damage is qualitatively different from low-LET radiation damage, as this severe dsb model may suggest, there could be far-reaching implications for the field of radiation protection.

The Paradoxical Nature of DNA Damage and Cell Death Induced by 125 I Decay

Chinese hamster ovary cells were synchronized at the G1/S-phase boundary of the cell cycle and pulse-labeled for 10 min with 125I-iododeoxyuridine 30 min after entering the S phase. Cell samples were harvested for freezing and 125I-decay accumulation at intervals ranging from 15 to 480 min after termination of labeling. The survival data showed a marked shift from cell killing characteristic of low-LET radiation to that more characteristic of killing by high-LET radiation with increasing intervals between DNA pulse-labeling and decay accumulation. Cells harvested and frozen within 1 h after pulse-labeling yielded a low-LET radiation survival response with a pronounced shoulder and a large D0 of up to 0.9 Gy. With longer chase periods the shoulder and the D0 decreased progressively, and cells harvested 5 h after pulse-labeling or later exhibited a high-LET survival response (D0: 0.13 Gy). Two interpretations for these findings are discussed. (1) If DNA is the sole target for radiation death, the results indicate that DNA maturation increases radiation damage to DNA or reduces damage repair. (2) If radiation cell death involves damage to higher-order structures in the cell nucleus, the findings suggest that newly replicated DNA is not attached to these structures during the initial low-LET period, but 125I starts to induce high-LET radiation effects as labeled DNA segments become associated with the target structure(s). On balance, or data favor the latter interpretation.

Genetic effectiveness of high-LET radiations

Genetic effectiveness of high-LET radiations

Alpha-particle-induced cancer in humans.

Updated information is given on alpha-particle-induced cancer in persons internally exposed to 222Rn progeny, Thorotrast, long-lived 226Ra and 228Ra, and short-lived 224Ra. The lung cancer risk to persons breathing 222Rn progeny in the indoor air of offices, schools, and homes is of increasing concern. About half of the recent deaths among the German Thorotrast patients have been from liver cancer. Animal studies indicate that the liver cancer risk from Thorotrast is mainly from its radioactivity and that the risk coefficient for the Thorotrast patients can be used provisionally for other alpha emitters in the human liver. Six skeletal cancers have occurred in persons with average skeletal doses between 0.85 and 11.8 Gy from 226Ra and 228Ra. In the low-dose German 224Ra patients, two skeletal sarcomas have occurred at about 0.7 Gy compared to about six cases predicted by results from 224Ra patients at higher doses. The minimal appearance time for radiation-induced bone sarcomas in humans is about 4 y. Following brief irradiation, the vast majority of induced bone sarcomas are expressed by about 30 y. Recent evidence against the "practical threshold" hypothesis is given. With the downward revision of neutron doses to the atomic-bomb survivors, the follow-up of persons exposed to alpha particles may be the best opportunity to evaluate directly the effects of high LET radiation on humans.

Analysis of High-LET Radiation Effects in Terms of Local Energy Deposition

There is now an emerging consensus amongst most biophysical models of radiation action that at low doses damage to mammalian cells is determined predominantly by very local properties of radiation interaction over distances of 1–100nm. Development and testing of models has been hampered by lack of detailed experimental data on the microscopic patterns of energy deposition over such small distances. More precise analysis has now become possible with the development of Monte Carlo techniques to simulate the tracks of charged particles interaction by interaction. To date, when such methods have been applied they have tended to confirm and emphasise further the importance of very local properties of energy deposition over 1–10 nm. Calculations of energy deposition in sub-cellular structures containing DNA by a particles, reveal the large amount of physical damage which mammalian cells can survive. Further identification is required of the critical stochastic physical and biological damage which is primarily responsible for altered cellular function.

Analysis of High-LET Radiation Effects in Terms of LocalEnergy Deposition

Analysis of High-LET Radiation Effects in Terms of LocalEnergy Deposition

Fast neutron radiotherapy: for equal or for better?

The renewed application of fast neutrons in clinical radiotherapy has been stimulated by fundamental radiobiological findings. The biological effects of high LET radiation, including fast neutrons, are different from those obtained with x rays in at least three respects: the oxygen enhancement ratio, the sensitivity of cells at different phases of the cell cycle, and the contribution of sublethal damage to cell reproductive death. Furthermore, wide variations in relative biological effectiveness (RBE) have been observed for different tumors and normal tissues. Measurements of volume changes in human pulmonary metastases indicate that the RBE for slowly growing tumors which are generally well-differentiated is higher than that for poorly differentiated lesions. Six thousand patients have now been treated with fast neutron beams. The results of the clinical applications vary according to the method of application and to the type of cancer involved: treatment of inoperable malignancies of the salivary gland is very encouraging: the therapeutic gain is rather small for bladder and rectal cancers, soft tissue sarcomas and advanced carcinomas of the cervix; the responses of brain tumors are very disappointing. Most neutron radiotherapy applications have been less than optimal because of inadequate physical and technical conditions. Despite these difficulties, some interesting clinical data have become available. Due to the technical shortcomings, the possible advantages of fast neutrons are probably underestimated for many tumor sites. Well-designed clinical trials, preferably performed with high energy cyclotrons in clinical environments, will provide a decisive answer to the question of the usefulness of the new radiation modality.

Studies of the effect of LET on the thermoluminescent properties of thin lithium fluoride layers

A limited assessment of the suitability of ultra-thin dosemeters using fine grains of lithium fluoride is described for future research into mixed radiation field thermoluminescence dosimetry. The differential response of the LiF was measured using alpha particles from 242Cm to study the effects of high LET radiation and 137Cs gamma radiation to study the effects of low LET radiation.

Biological effects of high LET radiation (January 21, 1977)

Biological effects of high LET radiation (January 21, 1977)Published Online:28 Jan 2014https://doi.org/10.1259/0007-1285-50-595-535SectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail AboutAbstractA high energy fast neutron beam potentially suitable for radiotherapy has been built at the Harwell variable energy cyclotron. Using 42 MeV deuterons on a “thin” (2 mm) beryllium target at 20/μA beam current the surface dose rate 150 cm from the target was about 60 rad/minute, and 130 rad/minute with a “thick” (4 mm) target. For the former the dose-rate decreased to 50% at depths of 11.3–15.4 cm in the phantom depending on field size. The use of mainly hydrogenous materials for shielding and collimation provided beam edge definition similar to that of 60Co teletherapy units, and off-axis radiation levels of about 1% which compares favourably with 14 MeV D-T generators. Previous article Next article FiguresReferencesRelatedDetails Volume 50, Issue 595July 1977Pages: 459-538 © The British Institute of Radiology History Published onlineJanuary 28,2014 Metrics Download PDF

Tomography: Its relevance and relative errors

In addition to basic physics and biology problems, and problems with the computation of high-LET radiation effects, detailed patient specification must be considered for treatment-planning purposes. This is more critical in high-LET work because of sharp dose gradients; for example, 60Co therapy central-axis dose fall-off is roughly 5% per centimeter, whereas fall-off could be as great as a 90% dose effect with pion therapy. Recent advances in tomography offer the promise of reaching the level of patient specification necessary for treatment planning. Conventional radiation therapy patient specification has been shown to have errors on the order of 2 cm, whereas computer-assisted tomography (CAT) has a resolution of about 2 mm. However, registration of CAT information for a patient in the treatment position may be the limiting factor (on the order of 0.5 cm). This technique will not account for patient movement, changes in patient definition due to bodily function, or changes due to irradiation over the course of treatment. Electrofluorotomography may solve some of these problems. This approach may provide registration information analogous to that currently provided by therapy simulators and verification analogous to therapy port films. Both of these tomography systems measure the dose absorbed through the patient from a low-energy X-ray spectrum. This has been shown to correlate best with electron density, but there are striking anomalies. It may be difficult to provide information on physical density or atomic number. Several radiation therapy groups are using CAT information directly for treatment planning. Improvements over conventional patient specification are highly site-specific. For the majority of treatments, the local efficiency and non-uniformity factors do not change in CAT-assisted plans.

Genetic Effects of High-LET Radiations in Mice

Despite pioneering work by Snell and Aebersold (1, 2) nearly thirty years ago, our ignorance of the genetic effects of high-LET radiations in mammals was until recently almost complete. Large-scale studies now in progress on the genetic effects of fast neutrons in mice are rapidly changing the situation, however, so that a fairly coherent picture of one aspect of this subject is already emerging. This picture is one of high genetic effectiveness under most, but not all, conditions of irradiation. In the present paper we shall give the latest results of our own work in this field, then shall discuss these results in conjunction with those of other workers. In this manner, we hope to arrive at an overall view of the present state of knowledge, especially with regard to the immature germ-cell stages which are most important from the standpoint of long-term risk to populations. Preliminary results of a comparison of the genetic effectiveness of chronic neutron and y-ray exposures have already been published (3), and a full account of this experiment will appear shortly (4).

THE RESPONSE OF MAMMALIAN TUMOR CELLS IN VIVO TO RADIATIONS OF DIFFERING IONIZATION DENSITIES (LET).

The response of mammalian tumor cells to ionizing radiation was studied in vivo, using the transplantability of leukemic ascites cells as a measure of cell-reproductive capacity. The relative effects of radiations having a wide range of ionization densities (LET) were assessed under oxygenated and anoxic irradiation conditions. Low-LET radiations give dose-response curves with a shoulder, indicating ability of cells to recover from sublethal irradiation effects when doses are fractionated, while highLET radiation produces an exponential survival curve and no recovery between fractions. Low-LET radiations are much influenced by the presence or absence of oxygen (oxygen-effect ratio 2.1: 2.3), while high-LET radiation effects are little modified by the presence or absence of oxygen (oxygen effect ratio 1.2). Finally, considerations for the use of high-LET (densely ionizing) radiations in radiotherapy of human cancer are discussed.