Health Effects of Exposure to Low Levels of Ionizing Radiations Time for Reassessment? (1998) / Chapter Skim
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3. Cellular and Molecular Considerations
3. Cellular and Molecular Considerations
Pages 14-29
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From page 14... ...
Changes in the normal sequences of bases in somaticcell DNA as a result of endogenous reactions or exogenous agents might alter the normally well controlled cellular processes and result in loss of homeostatic regulatory mechanisms, loss of inhibition or stimulation of cell growth and division, or cell death. The uncontrolled and metastatic growth of tumor cells, derived from previously normal cells, is associated with changes in DNA sequence in somatic cells.
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From page 15... ...
has estimated that about 1% of the oxygen consumed by human cells is diverted to oxidizing cellular protein and that 0.001% of the oxygen molecules damage DNA and RNA; these numbers undoubtedly increase under conditions of oxidative stress, such as during chronic inflammation. Although protein and small molecules, such as glutathione, serve as scavengers for reactive oxygen and thus protect the nucleic acids, there is a considerable amount of oxidative DNA-base damage per cell per day (Saul and Ames 1986~.
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From page 16... ...
~^~^~ ~ -are It has been argued in both the scientific and lay press that the quantity of spontaneous and metabolically generated DNA damage is many orders of magnitude larger than that resulting from low, protracted doses of radiation from environmental sources implying that the contribution from low doses of ionizing radiation is trivial (Biller 1990; Beckman and Ames 1997) -in other words, that the DNA damage produced by background radiation and the even higher doses to which some workers are exposed does not add appreciably to the extensive spontaneous and metabolic damage and can be ignored.
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From page 17... ...
radicals due to initial damage to molecules other than DNA (Floyd 1995; Milligan and others 1996~. Peroxy} radicals produce oxidized bases but not DNA strand breaks and might account for the greater-thanexpected yield of base damage, as opposed to strand breaks, observed in irradiated cells (Nackerdien and others 1992)
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From page 18... ...
Within the limits of detection of standard assays of DNA damage, induction of DSBs and other lesions in cellular DNA is generally found to depend linearly on radiation dose (lliakis and others 1992; Lange and others 1993~. Assays for the measurement of removal of base damage or the rejoining of SSBs or DSBs reveal that repair begins in cells as soon as radiation damage occurs.
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From page 19... ...
Alternatively, if the mismatch is not at the growing end of a DNA chain, mismatch-repair enzymes remove the wrong nucleotide, and the resulting gap in one strand is filled in properly by a DNA polymerase. Defects in the mismatch-repair enzymes have been associated with genetic instability and the human familial syndrome hereditary nonpolyposis colon cancer (Modrich 1994; Fishe!
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From page 20... ...
and not found as a segment of the background DNA damage, if the requisite repair enzymes do not require induction, and if the repair rate is not markedly altered as a function of dose, one could conclude that even the lowest dose of radiation can be biologically significant. in contrast, radiation damage can trigger a plethora of inducible processes, some of which can affect damage-recognition processes, repair, or the cellular responses to initial or unrepaired damage.
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From page 21... ...
A number of recently reported provocative phenomena in mammaTian cell systems deserve carefi~1 study to determine their biochemical mechanisms and possible relevance to the low-dose response to radiation and the question of linearity of that response. It has been shown, that in cultured human lymphocytes, low doses of radiation result in the "protection" of the cells from the chromosomal aberrations or mutations that would otherwise result from later exposure to radiation (Olivieri and others 1984; Sanderson and Morley 1986; Wiencke and others 1986; Kelsey and others 1991; Wolff 1992; Shadley 1994)
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From page 22... ...
In the case of Cockayne syndrome, characterized by deficiency in TCR, p53 and apoptosis are induced by much lower doses of radiation than in normal cells or in xeroderma pigmentosum complementation group C cells, which are proficient in TCR but deficient specifically in global genomic repair (Ejungman and Zhang 19961.
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From page 23... ...
The disruption of mismatch repair has been shown in a number of studies to enhance tolerance to DNA damage, including that produced by reactive oxygen species. Possibly the mismatch-repair system normally interferes with the processing, by nucleotide-excision repair, of some lesions produced by reactive oxygen species.
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From page 24... ...
1985; Winegar and Preston 1985~. The prevailing concept of the formation of chromosomal aberrations proposes that radiation induces two DSBs that interact with each other to produce aberration configurations-such as dicentrics, reciprocal transiocations, and rings-through incorrect rejoining of the broken ends.
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From page 25... ...
The increasingly refined methods of staining chromosomes, either by using prematurely condensed chromosomes (PCCs) or by chromosome painting, and the use of specific types of radiation, such as carbon K-characteristic x-rays, continue to provide newer insights into the mechanisms of formation of chromosomal aberrations.
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From page 26... ...
Attempts by groups of collaborating cytology laboratories to measure the dose-effect relationship for dicentrics at low doses have shown that linearity can be demonstrated down to 20 mGy but that at lower doses statistical variations mask any effect of radiation; measurements at doses below 20 mGy produced yields of dicentrics that were less than background but not significantly so (PohI-RuhI~g and others 1983; Lloyd and others 1988~. Those experiments did not reveal any evidence of a supersensitive response at the low doses; the researchers concluded that in view ofthe very large number of cells scored, it would be "very unlikely that the true response at doses less than 20 mGy will ever be measured directly with these techniques" Lloyd and others 1992~.
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From page 27... ...
Those results have been interpreted as implying "either that the participating DNA helices must be lying extremely close together at the time of radiation damage, so that one track can effectively damage bow helices, or that only one radiation-damaged chromosome is needed to promote an exchange event" (Thacker and others 1986~. The results appear, at first sight, to contradict the breakage-reunion concept of aberration formation, although explanations of the ultrasoft x-ray results have been sought in the application of"proximity" concepts to the breakage-reunion theory (Sachs and others 1997)
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From page 28... ...
Whichever hypothesis is finally shown to be correct, DNA DSBs and complex damage are currently the implied relevant radiation-induced lesions, and the dose-effect relationship at low doses is assumed by many to be linear. Mutations The type of mutation most o Den associated with radiation exposure is a large chromosomal deletion that can lead to the loss of the target gene and loss of additional DNA extending on both sides of the gene.
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From page 29... ...
Radiation leads to more transversion and frameshift mutations than are found spontaneously, but large intergen~c mutants occur spontaneously at a substantial frequency. The determination of quantitative dose-effect relationships is more difficult in the case of mutation than in the case of chromosomal aberrations but the measurements that have been made indicate a curvilinear relationship for sparsely ionizing radiation, in general, and a linear relationship at low doses (Cox and others 1977~.
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