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ScienceWeek
2004 25 June A6 6. MEDICAL BIOLOGY: ON RADIATION INJURY
In this context, the term "gray" (Gy) refers to the SI unit of absorbed dose of ionizing radiation, equivalent to 1 J/kg of tissue. 1 Gy = 100 rad. Named after Louis H. Gray (1905-1965), British radiologist.
The following points are made by C.N Coleman et al (Science 2004 304:693):
1) Ionizing radiation is present all around us; exposure to background radiation from cosmic rays and naturally occurring isotopes is unavoidable. We are exposed during diagnostic and therapeutic medical procedures and in certain occupations. Radiation therapy for cancer allows for precise, focused delivery, with improved quality of life; nonetheless, some exposure of normal tissue is unavoidable. As a result, many millions of cancer survivors will live for decades but will be at risk for adverse consequences such as tissue atrophy and secondary tumors (1). Further, the devastating events of 11 September 2001 underscore the potential for radiation exposure from nuclear and radiological terrorism, which could result in large-scale casualties from improvised nuclear devices or nuclear weapons (2-4).
3) The acute radiation syndrome (ARS) occurs after whole-body exposure to radiation doses greater than 1 Gy (gray). ARS is categorized into syndromes named for the organ system showing the most prominent symptoms. The central nervous system is affected within hours of exposures of more than 15 Gy, and fatalities occur within about 2 days. Gastrointestinal effects occur within a week after doses of 8 to 12 Gy; with only supportive care, most casualties will die within 10 days (4). After doses of 1 to 7 Gy, the hematopoietic (also lymphatic and immunologic) system syndrome appears in weeks to 2 months. Survival is likely at the lower end of this range and may be possible at the higher end with administration of cytokines, antibiotics, and fluids and electrolytes (4).
3) Radiation causes injury of normal tissue by a dynamic, evolving process involving cell killing, altered cell-to-cell communication, inflammatory responses, compensatory tissue hypertrophy of remaining normal tissue, and tissue repair processes (5). Changes in cytokines can be detected over time and radiation fibrosis may be partly reversible. The genetic characteristics of the exposed organism can influence the exact nature of the radiation response.
4) At present, no agents approved by the U.S. Food and Drug Administration are available for the treatment of ARS, although amifostine is approved for prophylaxis of dry mouth (xerostomia) from radiotherapy, and cytokines are used without approval for treatment of ARS. New research findings, however, promise improvements in survival after whole-body radiation and reductions in the risk of adverse effects of radiotherapy. The new approaches fall into one or more of several categories (3). Some of the substances act as free-radical scavengers (e.g., amifostine and tempol) and act on the initial radiochemical events. To be effective, they must be present at the time of irradiation and so must be administered before exposure. These compounds provide protection in a broad range of cellular and tissue systems.
References (abridged):
1. A. Trotti, Semin. Radiat. Oncol. 12 (suppl. 1), 1 (2002)
2. NCRP Report 138 (National Council on Radiation Protection and Measurements, Bethesda, MD, 2001).
3. J. E. Moulder, Int. J. Radiat. Biol. 80, 3 (2004)
4. R. C. Ricks, M. E. Berger, F. M. O'Hara, The Medical Basis for Radiation-Accident Preparedness: The Clinical Care of Victims (Parthenon, Boca Raton, FL, 2002)
5. H. B. Stone, C. N. Coleman, M. S. Anscher, W. H. McBride, Lancet Oncol. 4, 529 (2003)
Science http://www.sciencemag.org
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Related Material:
RADIATION RISKS, ALPHA PARTICLE EFFECTS, AND GAP JUNCTIONS
In addition to extracellular signaling pathways, some biological cells in tissues use an alternative communications system that involves direct movement of molecules from one cell to another. This type of communication is made possible by what are called "gap junctions", which permit small molecules to move directly from cell to cell without passage through the extracellular space. In thin-section electron micrographs, gap junctions appear as regions in which the plasma membranes of two adjacent cells are aligned in parallel and separated by a small gap of approximately 3 nanometers. The membrane surfaces in this region are covered by hundreds of resolved cylindrical structures called "connexons", and each connexon is apparently constructed from a single type of *transmembrane protein called "connexin". Gap junctions occur in almost every type of cell found in invertebrates and vertebrates, and they are especially abundant in tissues where extremely rapid communication between cells is required for optimal function. In heart tissue, for example, gap junctions facilitate the flow of electric current that causes the heart to beat. Several human diseases have been related to connexin mutations, including developmental anomalies of the cardiovascular system.
The following points are made by H. Zhou et al (Proc. Nat. Acad. Sci. 2001 98:14410):
1) Based principally on the cancer incidence found in survivors of the atomic bombs dropped on Hiroshima and Nagasaki, the International Commission on Radiation Protection and the US National Council on Radiation Protection and Measurements have recommended that estimates of cancer risk for low dose exposure be extrapolated from higher doses by using a linear no-threshold model. This recommendation is based on the dogma that the DNA of the nucleus is the main target for radiation-induced genotoxicity and, as fewer cells are directly damaged, the deleterious effects of radiation proportionally decline.
2) The authors used a precision microbeam to target an exact fraction (either 100 percent or <= 20 percent) of the cells in a confluent population, and irradiated their nuclei with exactly one alpha particle each. The authors report that the frequencies of induced mutations and chromosomal changes in populations where some known fraction of nuclei were hit are consistent with non-hit cells contributing significantly to the response. In fact, irradiation of 10 percent of a confluent mammalian cell population with a single alpha particle per cell results in a mutant yield similar to that observed when all of the cells in the population are irradiated. This effect was significantly eliminated in cells pretreated with a 1 millimolar dose of octanol, which inhibits gap junction-mediated intercellular communication, or in cells carrying a dominant negative connexin 43 vector.
3) The authors suggest the data imply that the relevant target for radiation mutagenesis is larger than an individual cell and indicates a need to reconsider the validity of the linear extrapolation in making risk estimates for low dose high linear-energy transfer radiation exposure. In summary: The results "provide clear evidence that a single alpha particle can induce mutations and chromosome aberrations in cells that received no direct radiation exposure to their DNA."
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Related Material:
MEASURING ONCOGENIC EFFECTS OF SINGLE ALPHA PARTICLES
Domestic exposure to radon gas in homes is generally considered to be the single largest naturally occurring environmental hazard. The basic mechanism involves DNA damage to *bronchioepithelial cells by alpha particles emitted by radon decay progeny. Recent estimates (1998) are that 10 to 14 percent of all lung cancer deaths in the US, or 15,400 to 21,800 deaths per year, are linked to radon gas exposure from the environment. At domestic exposure levels, the relevant bronchial cells are very rarely traversed by more than one alpha particle, whereas at higher radon levels these bronchial cells are frequently exposed to multiple alpha-particle traversals. It is at the higher radon exposure levels that epidemiological studies in uranium miners have allowed lung-cancer risks to be quantified with reasonable precision. Measuring the oncogenic transforming effects of exactly one alpha particle without the confounding effects of multiple traversals has hitherto been unfeasible, resulting in uncertainty in extrapolations of risk from high radon levels to domestic radon levels.
The following points are made by R.C. Miller et al (Proc. Nat. Acad. Sci. 1999 96:19):
1) The authors report a technique to assess the effects of single alpha particles on *cultured cells, the technique using a charged-particle microbeam which irradiates individual cells or cell nuclei with predefined exact numbers of particles. The authors report that although the technique was previously too slow in data acquisition to assess the relevant small oncogenic risks, recent improvements in the technique now permit microbeam irradiation of large numbers of cells, allowing the first oncogenic risk measurements for the traversal of exactly one alpha particle through a cell nucleus.
2) The authors report that in mouse *fibroblast cells the measured oncogenicity from exactly one alpha particle was significantly lower than that expected from statistical extrapolation, implying that cells traversed by multiple alpha particles contribute most of the risk. The authors suggest that if this result applies generally, extrapolation from high-level radon risks (involving cellular traversal by multiple alpha particles) may overestimate low-level radon risks (involving only single alpha particles).
Proc. Nat. Acad. Sci. http://www.pnas.org
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Notes by ScienceWeek:
bronchioepithelial cells: In animals, epithelial cells compose the cell layers that form the interface between a tissue and the external environment, for example, the cells of the skin, the lining of the intestinal tract, and the lung airway passages. The term "bronchioepithelial cells" refers to epithelial cells of the lung bronchi (lung airway passages).
cultured cells: In general, the term "cultured cells" refers to a population of cells maintained in vitro, the cells proliferating in a medium of controlled composition. In many experiments, the cultured cells are subpopulations of "immortal" cell lines widely used in numerous laboratories.
fibroblast cells: A type of connective tissue cell, secreting structural proteins (e.g., collagen) that form certain tissue components.
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