Low-dose ionizing radiation and chromosome translocations: A review of the major considerations for human biological dosimetry

Abstract

Chromosome translocations are a molecular signature of ionizing radiation exposure. Translocations persist significantly longer after exposure than other types of chromosome exchanges such as dicentrics. This persistence makes translocations the preferred aberration type for performing radiation dosimetry under conditions of protracted exposure or when exposure assessments are temporally delayed. Low doses of radiation are inherently difficult to quantify because the frequency of induced events is low and the background level of translocations among unexposed subjects can show considerable variability. Analyses of translocation frequencies can be confounded by several factors, including age of the subject, lifestyle choices such as cigarette smoking, the presence of clones of abnormal cells, and possibly genotypic variability among subjects. No significant effects of gender or race have been observed, but racial differences have not been completely ruled out. Translocation analyses may be complicated by the presence of different types of exchanges, i.e., reciprocal or non-reciprocal, and because translocations sometimes occur as a component of complex exchanges that include other forms of chromosome rearrangements. Rates of radiation exposure, ranging from acute to chronic, are known to influence the accumulation of translocations and may also affect their persistence. The influences on translocation frequencies of low-dose radiation hypersensitivity as well as the bystander effect and the adaptive response remain poorly characterized. Thus, quantifying the relationship between radiation dose and the frequency of translocations in any given subject requires attention to multiple issues. Part of the solution to understanding the in vivo dose–response relationship is to have accurate estimates of the baseline levels of translocations in healthy unexposed subjects, and some work in this area has been accomplished. Long-term cytogenetic follow-up of exposed subjects is needed to characterize translocation persistence, which is especially relevant for risk analyses. More work also needs to be done in the area of quantifying the role of known confounders. Characterizing the role of genotype will be especially important. Improvements in the ability to use translocation frequencies for low-dose biological dosimetry will require scoring very large numbers of cells per subject, which may be accomplished by developing a rapid automated image analysis system. This work would enhance our comprehension of the effects of low-dose radiation exposure and could lead to significant improvements in understanding the relationship between chromosome damage and human health.

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.