Biological Dosimetry in a Group of Radiologists by the Analysis of Dicentrics and Translocations

RADIATION RESEARCH

164, 612–617 (2005)

0033-7587/05 $15.00 q 2005 by Radiation Research Society.

All rights of reproduction in any form reserved.

Biological Dosimetry in a Group of Radiologists by the Analysis of Dicentrics and Translocations A. Montoro,a P. Rodrı´guez,b M. Almonacid,a J. I. Villaescusa,a G. Verdu´,c M. R. Caballı´n,d L. Barriosb and J. F. Barquinerod,1 a Servicio de Proteccio´n Radiolo´gica, Hospital Universitario La Fe, E-46009, Valencia, Spain; b Unitat de Biologia Cel·lular, Dpt. Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Cie`ncies, Universitat Auto`noma de Barcelona, E-08193, Bellaterra, Spain; c Dpt. Enginyeria Quı´mica i Nuclear, Escola Superior d’Enginyers Industrials, Universitat Polite`cnica de Valencia, E-46022, Valencia, Spain; and d Unitat d’Antropologia, Dpt. Biologia Animal, Biologia Vegetal i Ecologia, Facultat de Cie`ncies, Universitat Auto`noma de Barcelona, E-08193, Bellaterra, Spain

phases has provided the most reliable biological dosimetry, and it has been used widely for this purpose. This method has been used not only to assess acute doses but also to evaluate protracted doses like those received occupationally. Analysis of dicentrics is considered to be an important component of investigations of radiological exposures (1).

However, because dicentrics are unstable aberrations, cells carrying dicentrics are eliminated from the peripheral blood lymphocyte pool, and the dose estimated by dicentrics will therefore tend to decrease with time postirradiation (2, 3).

For past or chronic exposures, an alternative to the conventional use of dicentrics is the analysis of translocations.

After an exposure to ionizing radiation, translocations are induced at a frequency similar to that of dicentrics (4), but translocations are stable aberrations whose yield remains relatively constant over time (5, 6). Translocations can be detected easily by fluorescence in situ hybridization (FISH), and their analysis is a valuable tool in cases of old or longterm exposures (7, 8).

The present study was performed because lesions in the first three fingers from both arms, compatible with radiodermatitis, were detected in an interventional radiologist during the yearly medical examination of workers occupationally exposed to ionizing radiation. Due to the elevated yield of dicentrics detected in this radiologist (threefold higher than the background level), and to the anxiety in the rest of the group, a study analyzing dicentrics and translocations was carried out in nine individuals.

Montoro, A., Rodrı´guez, P., Almonacid, M., Villaescusa, J. I., Verdu´, G., Caballı´n, M. R., Barrios, L. and Barquinero, J. F. Biological Dosimetry in a Group of Radiologists by the Analysis of Dicentrics and Translocations. Radiat. Res. 164, 612–617 (2005).

The results of a cytogenetic study carried out in a group of nine radiologists are presented. Chromosome aberrations were detected by fluorescence plus Giemsa staining and fluorescence in situ hybridization. Dose estimates were obtained by extrapolating the yield of dicentrics and translocations to their respective dose–effect curves. In seven individuals, the 95% confidence limits of the doses estimated by dicentrics did not include 0 Gy. The 99 dicentrics observed in 17,626 cells gave a collective estimated dose of 115 mGy (95% confidence limits 73–171). For translocations, five individuals had estimated doses that were clearly higher than the total accumulated recorded dose. The 82 total apparently simple translocations observed in 9722 cells gave a collective estimated dose of 275 mGy (132–496). The mean genomic frequencies (3100 6 SE) of complete and total apparently simple translocations observed in the group of radiologists (1.91 6 0.30 and 2.67 6 0.34, respectively) were significantly higher than those observed in a matched control group (0.53 6 0.10 and 0.87 6 0.13, P , 0.01 in both cases) and in another occupationally exposed matched group (0.79 6 0.12 and 1.14 60.14, P , 0.03 and P , 0.01, respectively). The discrepancies observed between the physically recorded doses and the biologically estimated doses indicate that the radiologists did not always wear their dosimeters or that the dosimeters were not always in the radiation field. q 2005 by Radiation Research Society

MATERIAL AND METHODS INTRODUCTION

Blood Sampling and Culture

Since the early 1960s, cytogenetic dose estimation based on analysis of dicentric chromosomes in solid stained meta-

The study was approved by the Specialized Medical Safety Section of the Hospital la Fe in Valencia. Blood samples were obtained according to the general principles on health and safety at work in Spain, described in the law for prevention of risks at work published in the official state Gazette (BOE) on Friday 10th November 1995, BOE number 269, and the ‘‘Real Decreto’’ regarding health prevention against ionizing radiation published on Thursday 26th July 2001, BOE number 178. Before blood

Address for correspondence: Unitat d’Antropologia, Dpt. Biologia Animal, Biologia Vegetal i Ecologia, Facultat de Cie`ncies, Universitat Auto`noma de Barcelona, E-08193, Bellaterra, Spain; e-mail: francesc. barquinero@uab.es.

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collection, each individual signed an informed consent indicating that blood samples would be used only for the purpose of the study. Peripheral blood samples from radiologists in the same group, four females and five males with ages ranging from 43 to 57 years old, were collected by venipuncture in heparinized tubes. The subjects were exposed to X radiation over a period of 8–28 years and were routinely monitored with film badges or thermoluminescence dosimeters (TLDs). Procedures used by the group of radiologists were endoscopic retrograde cholangiopancreatography, pneumatic dilatation, and insertion of nasoenteric tubes or prosthesis in the gastrointestinal tract. The samples were cultured for 48 h in RPMI 1640 medium supplemented with 20% fetal calf serum, antibiotics and phytohemagglutinin. Bromodeoxyuridine at a final concentration of 39 mM was used in the setup of cultures. Colcemid was added 2 h before harvest.

Solid Staining and Fluorescence In Situ Hybridization For the analysis of dicentrics, 2- to 3-day-old slides were stained by the fluorescence plus Giemsa technique (9). For the FISH study, hybridization with Cy3-labeled probes for chromosomes 1, 4 and 11 and an FITC-labeled pancentromeric probe (Cambio, UK) was carried out as described previously (10). Counterstaining was performed with 49,6diamidino-2-phenylindole (DAPI) at a concentration of 1 mg/ml of antifade solution (Cambio, UK).

Scoring Criteria In the solid staining study, chromosome analysis was carried out exclusively on first-division complete metaphases. All metaphases with chromosome abnormalities were analyzed independently by two investigators. The chromosome-type abnormalities considered were dicentric chromosomes (dic) and rings (r) and were taken into account only when an acentric fragment was present. Acentrics not related to a dicentric or a ring were recorded as extra acentrics (ace).

In the FISH study, metaphases were examined using a triple-band pass filter, and the painted and unpainted chromosomes were analyzed using specific Cy3, FITC and DAPI filters. Once an abnormal cell was detected, pictures from each fluorochrome image were digitized using a Cytovisiont FISH workstation. To describe the aberrations involving painted chromosomes, a modification of the PAINT nomenclature (11) was used to consider the underlying mechanisms of aberration formation. A chromosome aberration was considered as complete when all painted portions were rejoined and as incomplete when one or more portions appeared to be unrejoined. Unstable aberrations (dicentrics, rings or extra acentric) affecting the painted and/or the counterstained portion were recorded, even in cells in which the painted portion did not show any chromosome aberration.

Comparisons with Controls The background frequency of dicentrics (0.91 6 0.03 3 1000 6 SE) obtained by the analysis of solid stained preparations from five females and seven males with ages ranging from 30 to 49 and no history of exposure to clastogenic agents (12) was used for comparison with the yield of dicentrics observed in the radiologists. The frequency of translocations observed in a matched control group of four females and five males studied previously (13), with ages ranging from 40 to 59 and no history of exposure to clastogenic agents, was used for comparison with the frequencies of translocations detected by FISH in the group of radiologists. In a previous study in which no radiologists were included, a slight but nonsignificant increase in the frequency of translocations was observed in hospital workers occupationally exposed to X and g rays (13). Because the mean annual dose received by this group (3 mSv) is similar to that recorded in the group of radiologists in the present study, the frequency of translocations observed in a matched group of five females and eight males from the previous study, with ages ranging from 40 to 53, was also used for comparisons. The comparisons were done using the Student’s t test.

RESULTS

In the nine individuals studied, a total of 7904 metaphases were analyzed in solid stained preparations and 9722 in FISH-stained preparations. When the frequencies of dicentrics detected by the two methods were compared (Table 1), no difference was observed in any case. For this reason and to reduce uncertainties in the dose estimations, all dicentrics were considered together (Table 1, last row).

Departures from Poisson distribution, assessed in terms of the test quantity U (14, 15), where a value of U greater than 1.96 indicates overdispersion at the 5% level of significance, were observed in individuals 4, 7 and 9, in whom one cell with four, two and two dicentrics, respectively, was observed. Individuals 1, 2, 3, 4, 7, 8 and 9 showed frequencies of dicentrics significantly higher than the background (P , 0.05). For these seven individuals, dose estimations using a previously established dose–effect curve for X rays (12) are shown in Table 2. Due to the disappearance of cells containing unstable aberrations with time postirradiation, dose estimations using dicentrics are suitable only to assess recent exposures. For this reason, a comparison with the recorded cumulative dose over the last 5 years is shown in Table 2. In six of these individuals (1, 2, 4, 7, 8 and 9), the cumulative dose recorded for the last 5 years was under the lower limit of the 95% confidence interval of the biologically estimated dose.

In Table 1, the number of apparently simple translocations observed by FISH is shown. A departure from Poisson distribution for total apparently simple translocations (AST) was observed in individual 7 due to a cell with two translocations, one complete and another incomplete. The mean percentage of incomplete translocations was 30%, similar to that described by others (4, 16, 17). Because most incomplete translocations are in fact complete (18), for dose estimations, a previously established dose–effect curve for AST was used (4). To consider the increase of translocations with age (19, 20), the yield of translocations observed in a matched control group was used as background (Table 3). Due to the combination of chromosomes (1, 4 and 11), the observed values were converted to full genome equivalent (FG) (21) using a factor of 0.314 in females and 0.318 in males. Assuming a chronic occupational exposure, the dose estimations have been calculated using the formula D 5 (Y 2 C/a), where Y is the observed yield of translocations and C and a are the background and linear coefficients of the dose–effect curve. The estimated doses (Table 2) were compared with the total accumulated recorded doses. In five individuals (1, 4, 6, 7 and 8), the biological estimated dose using AST was clearly higher than the accumulated recorded dose, especially for individual 8, for whom the translocation-estimated dose was about 400 mGy and the physically recorded dose was 2.2 mSv. The 99 dicentrics observed in 17,626 cells gave a collective estimated dose of 115 mGy (95% confidence limits 73–171), and the 82 AST observed in 9722 cells gave an

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TABLE 1 Chromosome Aberrations Detected in Solid and FISH-Stained Preparations Case

1

2

3

4

5

6

7

8

9

Solid stained preparations Cells analyzed Dicentrics Rings Extra acentrics

811 4 1 5

1008 5 1 10

1275 3 0 9

293 3 0 4

510 0 0 4

1000 3 0 5

1000 7 1 6

1006 6 0 5

1001 5 1 7

FISH-stained preparations Cells analyzed

1058

1096

1055

1000

1080

1025

1254

1001

1153

11

3

3

13

1

5

9

4

4

0 1 4 1

1 1 5 2

2 1 4 1

1 6 1

1

2

1 1 15 5 1 6 1

1

1

9 1 1 4 15 1 2 3 1

Chromosome aberrations Simple t(Ba) t(Ab) t(Ba) ace(b) t(Ab) t(Ba) ASTa dic(BA) ace(ab) dic(BA) ASDb r(B) ace(b) Complex dic(BA) t(Ab) t(Ba) ace(ab) ins(Aba) dic-dic(ABA) ace(b) dic-t(ABa) t(Ab) ace(ab) dic-ins(BAba) ace(ab) ace(b) dic(AA) ace(a) ace(a) Total cells Total dicentrics a b

15 2 2 1

2 11 1 1 2

3 7 4 1 5

1 1 1

1 1

1 5 2 1869 11

1 4 5 2104 10

1 3 5 2330 8

2 7 4 1293 17

2 0 1590 3

1 2025 5

2 8 7 2254 18

1 1 1 3 2007 13

2 2 2 2154 14

Total apparently simple translocations.

Total apparently simple dicentrics.

accumulated collective estimated dose of 275 mGy (132– 496).

The mean genomic frequency of complete and total apparently simple translocations observed in the group of radiologists has been compared with those observed in controls and in occupationally exposed individuals (13) (Table 3). The mean genomic frequencies (3100 6 SE) of complete and total apparently simple translocations observed in the radiologists were 1.91 6 0.30 and 2.67 6 0.34, respectively. These frequencies were significantly higher than those observed in the control group (0.53 6 0.10 and 0.87 6 0.13, P , 0.01 in both cases) and in the occupationally exposed group (0.79 6 0.12 and 1.14 60.14, P , 0.03 and P , 0.01, respectively).

DISCUSSION

The basal frequency in control individuals is one or two dicentrics per 1000 cells, and increased yields are related to the exposure to ionizing radiation. The group of radiologists evaluated in the present study showed a significantly higher frequency of dicentrics than controls (about six per

1000 cells). A significant increase of different types of chromosome aberrations compared to background levels has been described in several populations exposed occupationally to low and protracted doses of ionizing radiation (22–39). In these studies, significant increases in the yield of dicentrics were observed only in groups that included individuals with a high level of exposure ($200 mSv) (22– 25, 30, 32–36), whereas in groups with lower levels of exposure, differences were observed for acentric fragments, total chromosome aberrations, and total cells with aberrations (26–29, 31, 33, 36–39). The elevated yield of dicentrics observed in the group of radiologists from the present study are not in agreement with the physically recorded doses, where the average yearly dose received was 3 mSv and only one individual showed an accumulated dose higher than 200 mSv. The discrepancy between the physically recorded doses and doses estimated using dicentrics are even more pronounced when the cumulative dose over the last 5 years is considered. In this case, the biologically estimated doses are higher in individuals 1, 2, 3, 4, 7, 8 and 9.

Due to the inability of cells with unstable aberrations like dicentrics to divide, using them to monitor long-term ex-

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BIOLOGICAL DOSIMETRY IN A GROUP OF RADIOLOGISTS

TABLE 2 Physically Recorded Doses and Biologically Estimated Doses with 95% Confidence Limits Physical dose (mSv) Case

Years

1 2 3 4 5 6 7 8 9

22 8 13 25 17 27 28 23 27

a

Cumulative dose Accumulated dose over the last 5 years 75.2 21.3 60.2 228.1 10.7 5.5 105.8 2.2 115.2

27.6 20.8 16.4 7.7 4.8 0.6 12.9 0.5 8.7

Estimated dose (mGy) with 95% CL dicb 121 97 66 252

(52–203) (44–170) (14–132) (89–573) — — 163 (58–359) 134 (64–211) 134 (33–325)

ASTc 546 46 99 596 48 151 441 401 161

(236–940) (0–289) (0–376) (73–1710) (0–295) (0–467) (179–773) (125–777) (8–440)

Years of employment.

Estimated doses for dicentrics (dic), using the dose–effect curve: Y 5 (0.09 6 0.04) 3 1022 1 (3.43 6 0.68) 3 1022 D 1 (5.70 6 0.42) 3 1022 D2. c Estimated doses for total apparently simple translocations (AST) using the dose–effect curve: Y 5 (0.86 6 0.13) 3 1022 1 (6.57 6 1.06) 3 1022 D 1 (4.15 6 0.55) 3 1022 D2. a b

posures will tend to underestimate the dose. In the present study, the individuals analyzed had been involved in radiological procedures for a long period, from 8 to 28 years.

Because none of the monthly physically recorded doses for individuals 1, 2, 3, 4, 7, 8 and 9 indicated an overexposure, for a better assessment of past exposures, a FISH study to analyze translocations was carried out in all individuals.

In five of the individuals studied (1, 4, 6, 7 and 8), the doses estimated by translocations were higher than those estimated by dicentrics and ranged from 150 to 600 mGy, indicating that the overexposure detected is not only recent.

For individuals 2, 3, 5 and 9, no difference between doses estimated by dicentrics and translocations was observed.

The use of FISH techniques to measure transmissible chromosome aberrations for dose reconstruction has been used in several scenarios. Whereas in some studies the results were consistent with a long-term stability of translocations (5, 6, 40, 41), in others a temporal decline in the

translocation yield with time after the exposure has been suggested (42, 43). A possible explanation for this discrepancy is the difference in the initial dose of exposure. A study carried out in 10 individuals involved in the Goiaˆnia accident (44) indicated that the FISH method is feasible for exposures below 0.5 Gy. In a cytogenetic follow-up study of some highly irradiated victims of the Chernobyl accident, the FISH method was still feasible for doses below 3Gy (45). Because the estimated total accumulated doses in the present study are below 1 Gy, it can be assumed that they are close to the unknown real doses.

Another factor that influences the persistence in the yield of translocations is whether the exposure affects the whole body homogeneously (46). Procedures used by the group of radiologists studied included radiography fluoroscopy and cineradiography, which implies exposures to relatively high levels of scattered radiation and a non-uniform body distribution of the dose (47). After a whole-body exposure

TABLE 3 Complete and Total Apparently Simple Translocations Detected by FISH in Control and Occupationally Exposed Groups and in the Group of Interventional Radiologists of the Present Study

Number of individuals Sex ratio Age range Mean accumulated dose received 6 SE (mSv) Mean years of employment Cells analyzed Equivalent cellsa t(Ba) t(Ab) FGb 6 SE AST FGb 6 SE a b

Control

Occupationally exposed

Radiologists

9 4F/5M 40–59 — — 13204 4179 22 0.53 6 0.10 36 0.87 6 0.13

13 5F/8M 40–53 45.5 6 7.6 17 6 2 19827 6279 49 0.79 6 0.12 71 1.14 6 0.14

9 4F/5M 43–58 69.4 6 24.5 21 6 2 9722 3077 58 1.91 6 0.30 82 2.67 6 0.34

(cells from males 3 0.318) 1 (cells from females 3 0.314).

Observed number of translocations divided by equivalent cells (3100).

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MONTORO ET AL.

to low-LET radiation, the distribution of both dicentrics and translocations should follow a Poisson distribution. For dicentrics, the overdispersion observed in individuals 4, 7 and 9 suggests a non-uniform exposure. In individual 9, for whom the doses estimated by dicentrics and translocations were very similar, the overdispersion can be attributed to a recent non-uniform exposure. In this case, using the calculational approaches developed to be applied in cases with overdispersion (1), the partial-body doses estimated by the contaminated Poisson method were 1.34 Gy and 1.02 Gy using the Qdr method. By FISH, because only part of the genome is analyzed, the ability to detect deviations from Poisson in the translocation cell distribution is reduced (48), and only individual 7 showed an overdispersion for AST. In this case the dose estimated by the contaminated Poisson method was 2.53 Gy. As a group, the frequencies of chromosome aberrations observed by solid staining or FISH were higher than those observed in controls and in hospital workers occupationally exposed to ionizing radiation with similar physically recorded doses. This indicates that some radiologists were exposed to higher doses of radiation. The collective dose estimated by dicentrics was 115 mGy, about twice the mean of the physically recorded doses. Since dicentrics may be lost during the exposure period, the dose estimated by dicentrics is in fact an underestimation of the real dose. When AST are considered, the collective estimated dose was 275 mGy. In this case, the discrepancy between the physically recorded and the biologically estimated doses increases by a factor of 4. The reasons for such discrepancy may be that radiologists did not always wear their dosimeters or that in most cases the dosimeters were not in the radiation field, which implies a possible partial-body exposure. In fact, in some cases the cytogenetic results showed a non-uniform exposure, and the partial dose received would probably be 1–2 Gy. Elevated frequencies of dicentrics in six cardiologists and staff members have also been reported recently (38).

Although chromosome analyses has been used mainly as a biomarker of genotoxic agents, there is accumulating evidence of an association between the increased level of chromosome aberrations in peripheral blood lymphocytes of healthy individuals and the risk of cancer (49). There is an increased interest in improving radiation protection in interventional radiology, especially in light of more complex procedures and the expansion of the indications, hence increasing fluoroscopy times and dose (50). The observation of an elevated yield of aberrations not only in the individual with radiodermatitis but also in the majority of members of the group indicates the need to minimize individual exposure to X rays during radiological procedures.

Moreover, as suggested by Zakeri and Assaei (38), people involved in such medical examinations should receive periodic training in radioprotection. Cytogenetic studies, including FISH techniques, should be extended to more ra-

diologists, nurses and technicians to assess the risk derived from their occupational exposure.

ACKNOWLEDGMENTS This research was supported in part by the Spanish Consejo de Seguridad Nuclear SPR/316/99/640 and by the Generalitat de Catalunya 2001SGR 00213.

Received: November 11, 2004; accepted: June 6, 2005

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