Mutation Research/Reviews in Mutation Research
ReviewLow-dose ionizing radiation and chromosome translocations: A review of the major considerations for human biological dosimetry
Introduction
Chromosome aberrations have been widely accepted for many years as a biological marker of exposure for ionizing radiation. Recent evidence indicates that aberrations are also a biomarker of effect because groups of individuals with elevated aberration frequencies have increased risks of cancer. Ionizing radiation is a potent inducer of chromosome rearrangements, and high doses of radiation are carcinogenic. Less certainty exists concerning whether low doses of ionizing radiation are also carcinogenic. The past two decades have seen significant improvements in the ability to identify and quantify chromosome damage, of which the most notable development has been fluorescence in situ hybridization (FISH) with whole chromosome paints. FISH painting can identify translocations (symmetrical exchanges in which each resultant chromosome has one centromere) as readily as dicentrics (asymmetrical exchanges resulting in a chromosome with two centromeres and an acentric fragment). The ability to identify translocations with high accuracy and efficiency is significant because translocations have substantially greater persistence through cell division than dicentrics [1], [2]. This stability of translocations makes them the preferred marker for radiation exposures that are chronic or that occurred many years previously. Dicentrics remain the aberration of choice when exposures are at least moderately acute and recent, i.e., within the last few weeks or months. Painting for translocation identification has a significant order-of-magnitude advantage compared to conventional cytogenetic methods with respect to analysis speed. The use of translocations for biodosimetry has increased over the past decade with the commercial availability of reliable whole chromosome painting probes and with investigators’ familiarity with in situ hybridization methods.
A number of observations support the idea that translocations may be the most relevant cytogenetic endpoint for assessing cancer risks. These include the wide-spread acceptance of translocations as a biomarker of exposure to ionizing radiation [3], [4], [5], [6], [7], [8], [9], the evidence that chromosome aberration frequencies may be elevated as a result of exposure to chemicals such as cigarette smoke, e.g. [10], [11], [12], [13], the recent findings that aberrations are associated with increased risks of cancer [14], [15], [16] and the observation that essentially all types of cancer cells bear translocations [17], [18], [19].
Low doses of ionizing radiation (<1 Gy) comprise the vast majority of exposures, which occur most often in occupational settings or as a result of contamination from environmental accidents such as Chernobyl, e.g. [20], [21], [22], [23], [24], [25], [26]. Such exposures are most often chronic or highly fractionated. Medical exposures such as diagnostic X-rays also occur and generally consist of very low doses (<1 cGy); with current technologies these have been regarded as nearly inconsequential in terms of the overall amount of radiation received and their effects on cytogenetic measurements. However, recent evidence suggests that the lifetime accumulation of personal diagnostic X-rays may result in detectable levels of translocations [27]. High exposure-doses (>1 Gy) are rare and will not be emphasized in this paper.
Section snippets
Types of translocations
For many years, chromosome exchanges including translocations were thought to involve exactly two chromosomes. More recent evidence indicates that complex aberrations, which involve two or more breaks in three or more chromosomes [28], are surprisingly common. Complex aberrations arise from simultaneous double strand breaks in multiple chromosomes followed by a multi-way exchange [29], [30], [31]. Both the prevalence and the complexity of multi-way exchanges increase with dose, especially above
Low-dose radiation hypersensitivity
Low doses of ionizing radiation are inherently more difficult to detect and quantify than high doses. Of interest to some investigators has been the question of whether there is a threshold below which ionizing radiation does not induce chromosome aberrations. Although the ultimate answer to this question can only be determined by evaluating the biological effects of the absorbance of a single photon or particle by a cell, the preponderance of evidence obtained from dose–response curves
Induction, accumulation and persistence of translocations
The concepts of induction, accumulation and persistence are important for understanding the effects of exposure to ionizing radiation. Induction refers to the initial formation of translocations immediately following exposure. Each dose or dose fraction, no matter how small or large, has the potential for inducing double strand breaks that lead to translocations. In the case of multiple exposures, aberrations may be induced as a result of each exposure. Accumulation is the acquisition of
The importance of cell type upon translocation frequencies
The persistence of translocations depends in part on the type of cells evaluated. Most human exposure evaluations are performed using peripheral blood T lymphocytes, which have a half-life in vivo of several months to a year [54], [55]. Evaluating chromosomes in these cells is achieved by culturing whole blood (or occasionally isolated lymphocytes) in the presence of a mitogen, commonly phytohemagglutinin, which stimulates lymphocytes to divide in vitro. Without such stimulation the lymphocytes
Dose rates and translocation persistence
What do dose rates have to do with translocation persistence? As already noted, chronic (or fractionated or intermittent) exposures generally result in simpler aberrations than acute exposures. Since simpler aberrations are less likely to be cell-lethal, cells with translocations that were induced by chronic exposure may be more likely to survive than cells with translocations induced by acute exposure. Most human exposures involve chronic low doses, so it is reasonable to expect that
Translocation frequencies in subjects not exposed to ionizing radiation
As with other types of genetic damage, cells with chromosome translocations are observed in somatic cells at low frequencies in unexposed humans. If sufficient numbers of cells are examined, virtually every adult has one or more peripheral blood lymphocytes with some type of translocation. Reasoning that the stability of translocations should be consistent with their accumulation with age, our laboratory set out some years ago to determine whether translocations would accumulate in normal,
Influences of confounding factors upon translocation frequencies
Since it is clear that translocations arise from a variety of known and unknown sources, it is relevant to consider the variables that could confound the analyses of subjects potentially exposed to low doses (<1 Gy) of ionizing radiation. As indicated above, aging is the variable with the largest effect. In the study by Ramsey et al. [10], aging accounted for 70% of the statistical variation. Other studies have not explained this much of the variance, probably because a narrower range of ages
Improving the assessment of low doses of radiation
Exposure to low doses of ionizing radiation is a fact of life in certain occupational settings. Radiation accidents, while unfortunate at the minimum and devastating in the worst cases, will no doubt continue to occur. Fortunately most radiation exposures involve low doses (≪1 Gy) and as such do not have immediate life-threatening effects. However, long-term effects of low-dose exposures, especially the potential for increased risks of cancer, may be real and should be given serious
Recommendations for the future
To facilitate the extensive research suggested above, an effort should be made to develop the hardware and software needed to conduct that work in an optimal manner. The rate-limiting and most expensive component of population-based molecular cytogenetic analyses is the cost of the human labor needed to perform the microscope work. Minimizing the labor costs could be achieved through the use of automation. A fully automated system would involve machine-loading of hybridized slides onto the
Summary
Most human radiation exposures involve doses that are chronic or highly fractionated and are substantially below 1 Gy. The long-term goal of cytogenetic analyses should be to assign reliable risk estimates to individuals, something that is currently available only at the population level. When assigning doses to individual subjects an ever-increasing number of variables will need to be taken into consideration. Currently these include age, tobacco use, dose rate, time elapsed since the end of
Acknowledgments
The author wishes to thank R. Thomas, D. Petibone, and S. Gajapathy for critical review of the manuscript.
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