Mutation Research, 260 (1991) 239-246 © 1991 Elsevier Science Publishers B,V. 0165-1218/91/$03.50 ADONIS 0165121891001028

239

MUTGEN 01667

Genotoxic and mutagenic effects of the diagnostic use of thallium-201 in nuclear medicine Karl T. Kelsey 1,2, Kevin J. Donohoe 3, Barbara Baxter 1, Asli Memisoglu 1, John B. Little 1, Michele Caggana 1 and Howard L. Liber 1 I Laboratory of Radiobiology and 2 Occupational Health Program, Harvard School of Public Health and 3 Department of Radiology, Division of Nuclear Medicine, Beth Israel Hospital, Boston, MA 02215 (U.S.A.)

(Received 16 July 1990) (Accepted 21 December 1990)

Keywords: Thallium-201; Hprt mutation; Chromosome aberrations

Summary In order to investigate possible mutagenic effects of in vivo exposure to low levels of ionizing radiation used in nuclear medicine, we have examined the hypoxanthine guanine phosphoribosyl transferase (hprt) mutant fraction (MF) and chromosome aberration (CA) frequency in 24 nuclear medicine patients before and after injection of thallium-201. The mean M F of the thallium-201-exposed cohort was 5.2 + 4.4 x 10 - 6 before injection exposure. No significant difference in MF was observed 24 h later. In 11 patients who were studied on a third occasion, 30 days after thallium-201 exposure, there was again no significant difference in post-exposure as compared with the pre-exposure MF. The frequency of CA in peripheral blood lymphocytes was not significantly different, comparing pre- and 24 h to 1 month post-radionuclide exposure. Thus, thallium-201 exposure was not associated with significant elevations in M F or CA frequency in lymphocytes of exposed individuals.

Ionizing radiation has become an important clinical tool for both medical diagnosis and therapy. However, due to the ability of ionizing radiation to induce cellular damage, there is some level of risk for the development of genetic damage after radiation exposure to the patient. Despite much research over the last few decades, there remains considerable uncertainty as to the genetic

Correspondence: Dr. K.T. Kelsey, Occupational Health Program, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02215 (U.S.A.).

impact of ionizing radiation on human populations, particularly at low levels. Currently there are many radiopharmaceuticals in clinical use; ongoing research will undoubtedly result in an increase in the number of such agents. The principal aim in designing a diagnostic radiopharmaceutical is to produce a compound which will selectively concentrate in the target tissue and then decay or be eliminated rapidly following data collection. Many isotopes used for diagnostic purposes decay by electron capture or isomeric transition, with the production of a y ray which is used in imaging. Some of these radionuclides also de-

240

posit a portion of the decay energy as a shower of low-energy Auger electrons of very limited range. These electrons arise from a complex series of both radiative and non-radiative transitions resulting from inner electron shell vacancies in the daughter atom. When Auger electron-emitting radionuclides decay in biological systems, extensive molecular damage occurs in the immediate vicinity (10-50 A), with the damage resembling that produced by high linear energy transfer (LET) radiation. Thus, estimation of the biological effects of diagnostic radionuclides must include evaluation of the effects of the Auger electrons as well as the low-LET "f ray. The extreme cytotoxicities of clinically used . . . . 51 125 75 Auger-elrnttmg nuclides (including Cr, I, Se and 7VBr) have been well characterized using mammalian assays (Hofer and Hughes, 1971; Burki et al., 1973; Bradley et al., 1975; Hofer et al., 1975; Chan et al., 1976; Harbottle et al., 1976; Warters et al., 1978; Kassis and Adelstein, 1980; LeMotte and Little, 1983; Liber et al., 1983; Little et al., 1983; Kassis et al., 1985, 1986; Lavu et al., 1985). Toxicity is highly dependent upon the intracellular location of the nuclide, with nuclear localization necessary for the induction of genetic damage. These observations recently have led some professionals to question the appropriateness of conventional dosimetry in estimating cellular exposure after administration of these radionuclides (Gaulden, 1983; Editorial, 1985). Thallium-201 decays by electron capture and internal conversion to Hg-201 with the emission of a shower of Auger electrons (approximately 21 electrons per decay). It is very radiotoxic to both mammalian germ cells in vivo and somatic cells in vitro (Rao et al., 1983; Kassis et al., 1983). Thallium-201 behaves like a potassium cation in vivo and, therefore, is highly concentrated throughout cells, including inside the nucleus (Kassis et al., 1983). Hence, 2roT1 clearly has the potential to induce significant genetic damage to exposed cells, including lymphocytes. Studies of individuals exposed to very low doses of high-LET emitters such as radon and plutonium (c~ sources) as well as therapeutic exposure to Thorotrast (232Th decay series, primarily c~ emitters) have shown that exposure only slightly above background is capable of signifi-

cantly elevating the chromosomal aberration frequency in peripheral lymphocytes (Tawn et al., 1985; Brandon and Bloom, 1983; Pohl-Ruling and Fischer, 1983: Ishihara and Kumatori, 1983). These findings are consistent with in vitro studies that show the high clastogenic potency of highLET radiation (Davy, 1969; Lloyd et al.. 1973: Hall et al., 1975; Evans et al., 1979; Edwards et al., 1980; Roberts and Holt, 1982, 1985: Roberts et al., 1987). Data on the clastogenicity of incorporated radionuclides are very limited. Radiolabeling of peripheral blood lymphocytes with indium-Ill oxinate, a lipophilic chelate of I n - l l l used clinically to study lymphocyte kinetics and cellular localization, has been shown to induce severe chromosomal damage (with aberrations in 95% of labeled lymphocytes) at doses normally used for imaging (Ten Berge et al., 1983). I n - l l l emits Auger electrons with an energy between 0.6 and 25.4 keV with a tissue range of 0.025 12.55 /xm. As a lipophilic chelate, it binds irreversibly to cytoplasmic and nuclear components of the cell (Thakur and McAfee, 1984). Technetium-99m, which is the most widely used radionuclide in nuclear medicine, has also been found to induce a high degree of cytogenetic damage in stannous chloride-labeled lymphocytes at clinically used doses (Merz et al., 1986). Thallium-201, thallous chloride, has a half-life of 3.08 days and is clinically used to image myocardial blood flow. During stress, increased myocardial oxygen needs are met by local regulatory mechanisms which increase myocardial perfusion. If a section of myocardium is supplied by a stenotic coronary artery, that portion of myocardium will be unable to increase blood flow to the extent that a section of myocardium supplied by a normal coronary artery can. This discrepancy in perfusion is manifest as an inequality in thallium distribution noted in the nuclear medicine image. To investigate the in vivo genotoxicity of exposure to diagnostic radionuclides, we have studied a cohort of nuclear medicine patients exposed to thallium-201. As genetic endpoints, we have assessed structural chromosome damage in peripheral blood lymphocytes and used T-lymphocyte cloning for quantification of 6-thioguanine-

241 resistant mutants, which is representative of cells with mutations at the hypoxanthine guanine phosphoribosyl transferase (hprt) locus. Methods

Subjects Volunteer patients scheduled to undergo 2°1T1 nuclear medicine imaging at the Beth Israel Hospital (Boston, MA) were eligible for the study. All patients were given an extensive questionnaire to collect demographic data as well as their occupational and medical history and a history of their habits, including diet, smoking and alcohol use. None of the patients was taking any medication known to be mutagenic or carcinogenic. Blood was drawn from each individual immediately before radionuclide injection and studied as a baseline. After injection of thallium-201 but before appreciable renal clearance (at 60 min) blood was again drawn. This sample, along with the pre-injection blood sample, was stored at room temperature overnight to allow for additional exposure to the radionuclide (this second sample is termed the 24-h time point). Samples were placed into culture after 24 h since longer storage would adversely affect lymphocyte growth, and thus this 24-h exposure of the stored cells to decaying 2°~T1 represented the optimal cellular exposure to Auger decay. The dose to the lymphocytes under these conditions is about 10 times higher than the dose to lymphocytes remaining in circulation, due to the 6-h renal clearance half-time. In addition, of the 24 volunteers studied before injection and 24 h after injection, 11 individuals were able to return for a repeat blood sample 1 month after radionuclide exposure. One month was chosen as a follow-up time since other work has suggested that this is sufficient time for full expression of in vivo mutation (Messing and Bradley, 1985). Only those individuals who had received no mutagenic drugs or therapies were included in the 1-month post-exposure blood set.

T-cell cloning assay The assay utilized was a variation of the method of O'Neill et al. (1987). Twenty-four hours after

receipt of peripheral blood, T-lymphocytes were isolated by dilution with Earle's balanced salt solution (EBSS), and centrifugation on 4 ml of Ficoll (mol. wt. 400,000) Hypaque-M 90% (Pharmacia LKB, Piskataway, N J) at 750 rpm for 30 min at room temperature. The mononuclear cell fraction was washed once in EBSS. The washed pellet was then resuspended in RPMI 1640, supplemented with 25 mM Hepes, 2 mM L-glutamine, 100 units/ml penicilhn and 100 /~g/ml streptomycin sulfate. The medium was supplemented with 10% pre-screened fetal calf serum (Armour Pharmaceuticals, Kankakee, IL) and 20% HL-1 nutrient medium (Ventrex Laboratories, Portland, ME) and hand-counted on a hemocytometer. The cells were diluted to a density of 106 cells per ml and supplemented further with 1/~g/ml of purified phytohemagglutinin (PHA-P, Burroughs-Wellcome Co., Research Triangle, NC). The cultures were incubated for 36-40 h in flasks at 37°C in humidified incubators with a 5% CO 2 atmosphere in air. The cultures were then gently agitated, and the cells were centrifuged and resuspended in the above media supplemented with 20% T-cell growth factor. The growth factor used was the generous gift of Drs. Timothy Eberlein and Deric D. Schoof (Brigham and Women's Hospital, Boston, MA). The growth factor was the supernatant generated from the lymphokine-activated killer cell immunotherapy protocols utilized at this facility. At plating, the medium was supplemented with 0.125/~g/ml PHA-P. The cells were seeded at 2, 5, and 10 cells per well in non-selective medium along with 10 4 irradiated feeder cells (5000 cGy, cobalt-60 y rays delivered at approximately 20 cGy/sec). The cells were plated in 96-well roundbottom microtiter plates at a volume of 0.2 ml per well. The feeder cells, designated X3C, are an HPRT-deficient line which have a total gene deletion. These feeder cells were grown in RPMI 1640 supplemented with 10% horse serum. For selective conditions, 2 × 10 4 cells per well were seeded in complete medium containing 20 /~M 6-thioguanine along with 104 irradiated feeder cells per well. The cells were plated in 96-well flat-bottom microtiter plates at a volume of 0.2 ml per well. The plates were incubated for 10-14

242 days to allow for colony growth. Plates were counted twice during this period with a 10 × objective and scored as positive or negative for colony formation. Cloning efficiencies were calculated according to Poisson statistics, Po = e -', where x is the average number of clonable cells per well and Po is the observed fraction of negative wells. The MF is the ratio of cloning efficiency in the presence of 6-thioguanine to the absence of 6-thioguanine.

Chromosome aberration determination Whole-blood cultures were initiated in duplicate from blood drawn before 2roT1 injection, from the post-injection blood draw (24 h) and from blood drawn 1 month after 2roT1 injection. The remainder of the sample of heparinized blood was used for mutagenicity assays. Whole blood (0.5 ml) was added to a 5-ml volume of RPMI 1640 culture medium with L-glutamine containing 10% fetal calf serum, 1% phytohemagglutinin, penicillin (100 units/ml), and streptomycin (100/,g/ml). 50 t~g 5-bromodeoxyuridine was also added to the culture medium 24 h after initiation of duplicate cultures. Cultures were incubated for 48 h in complete darkness at 37°C in an atmosphere of 5% CO2/95% air. Colcemid (0.1 # g / m l ) was added to each culture 2 h before processing. The lymphocytes were harvested and treated with 10 ml of hypotonic KC1 (75 mM) for 8 min. Cells were then fixed at ambient temperature in freshly prepared methanol:glacial acetic acid (3:1, v/v). The cell suspension was washed twice in fixative and slides were prepared by an air-dry technique. The slides were differentially stained to facilitate analysis of first-division mitoses by a modification of the fluorescence-plus-Giemsa technique of Perry and Wolff (1974). Each slide was stained for 10 min in Hoechst 33258 (5 ~tg/ml) in double-distilled water and mounted in a phosphate buffer (pH 6.8). The slides were then exposed to black light from two 15-W tubes for 10 rain at a distance of 1.0 cm and stained with 5% Giemsa in phosphate buffer (pH 7.0) for 3 min. One reader blindly scored all of the first-division metaphases. Only complete metaphases were scored (45-47 centromeres); for each individual 200 cells per point were analyzed.

Statistical analysis Analysis of variance (ANOVA) was used to c o m p a r e both the c h r o m o s o m e aberration frequency and mutant fraction before and after exposure to 2{nT1. Results and discussion

Estimation of dose Low-energy Auger electrons deposited outside the cell contribute little to cytotoxicity, while Auger emitters decaying within the cell can frequently be cytocidal. Many details about the effects of internally deposited 2°1T1 on lymphocytes have yet to be elucidated; however, data obtained through work with other cell types can be used to estimate the radiation dose to lymphocytes. Each subject was injected with 2-3 mCi of 2°1T1. For the radiation dose calculation, we have assumed that the lymphocytes were exposed in a fashion similar to the spleen (both are parts of the blood pool) and that the mean disappearance time of the tracer from the body was 10 h (Chilton et al., 1990). Initially we also assumed that the values in the Medical Internal Radiation Dose (M1RD) tables can be applied to lymphocytes. From the M I R D tables a dose of 1.62 cGy to the lymphocytes can be derived. However, recent calculations demonstrate that conventional dosimetry may underestimate the microdosimetry for 2roT1 by 2 25-fold (Makrigiorgos et al., 1989). Therefore, the dose to the lymphocytes may range from 3.25 to 40.5 cGy. Chromosome aberrations In the parallel chromosome aberration studies, the mean aberration frequency in lymphocytes exposed for 24 h to thallium-201 did not differ from the pre-exposure mean aberration frequency ( p > 0.05, ANOVA). In addition, no significant differences in aberration frequency between preand post-thallium exposure were observed in any one individual studied. In the individuals restudied at 30 days, there was a suggestion of a small increase in aberration yield, although this was not statistically significant when analyzed using ANOVA (Table 1). It seems unlikely that 2°1T1 induced significant chromosomal damage in lymphocytes especially since there was no ap-

243 TABLE 1 FREQUENCY OF CHROMOSOME-TYPE ABERRATIONS IN FIRST-DIVISION METAPHASES BEFORE AND AFTER THALLIUM-201 EXPOSURE Subject

Before

After 24 h

After 1 month

Metaphases

Total

Metaphases

Total

Metaphases

Total

examined

aberrations

examined

aberrations

examined

aberrations

1 2 3 4 5 6 7 8 11 12

200 200 200 200 200 200 200 200 200 200

1 2 1 1 0 1 0 0 0 0

200 200 200 200 200 200 2o0 200 200 200

1 2 1 0 1 0 1 2 1 l

200 200 200 200 200 20o 2o0 200 200 200

1 1 1 3 0 1 1 4 2 1

Total

2000

6

2000

10

2000

15

parent effect of this radionuclide at the 24-h time point (when chromosomal damage should be maximal).

In vivo mutant frequency 201

Twenty-four Tl-exposed individuals were sampled before and after radionuclide exposure and 11 of these were re-studied 1 month later. As is seen in Table 2, the mean pre-exposure mutant fraction (MF) did not significantly differ from the mean 24-h post-imaging MF in the 2mTl-exposed cohort ( p > 0.05, ANOVA). In addition, the M F in patients studied 1 month after 2roT1 injection did not differ significantly from either the pre- or post-injection MFs ( p > 0.05, ANOVA). The mean mutant fraction observed in the patients exposed to thallium-201 was similar to that which we have observed in a healthy reference population in our laboratory. In 71 individuals we observed a mean MF of 4.6 + 4.3 X 10-6; there was a significant increase in MF associated with smoking, but not with age or gender (Caggana et al., 1990). As a positive control, we have studied patients with Hodgkin's disease who were treated therapeutically with X-rays. These patients each received approximately 30-40 Gy, primarily to their para-aortic lymph nodes. As is shown in Table 3,

this treatment significantly induced hprt mutations in this group of 6 patients, when compared to the pre- or post-treatment MF of the patients given 201 T1 ( p < 0.01, ANOVA). Utilizing the same techniques of human peripheral blood lymphocyte cloning, Seifert et al. (1987) published a study of mutations induced in 10 nuclear medicine patients. These investigators reported that exposure to 1-1.5 cGy of ~, radiation from technetium-99m induced an average 3.5-fold increase in mutant frequency. Increased mutant frequencies were observed in 9 of 10 patients. This increase was also expressed as a yield of 3.7-5.5 × 10 6 induced m u t a n t s / c e l l / c G y . This is surprisingly high. Experimental work in lymphocytes in vitro with low-LET radiation (X or y rays) has yielded rates of 2 - 5 × 10 -7 m u t a n t s / c e l l / c G y (Vijayalaxmi and Evans, 1984; O'Neill et al., 1990). In both of these latter studies, little or no mutation was observed at lower doses (0-50 cGy). Furthermore, Messing and Bradley (1985) showed that breast cancer patients treated with y radiation had an average induced mutant fraction of about 7 × 10-8 m u t a n t s / l o c u s / c G y . In previous experiments which studied the effects of 125I (an Auger-emitting radionuclide) bound to DNA, Whaley and Little (1990) and Liber et al. (1983) have reported Auger decay to

244 TABLE 2 IN VIVO hprt MUTANT FRACTION (MF) BEFORE AND AFTER THALLIUM-201 EXPOSURE Subject

Before

After 24 h

M F ( × I 0 - 6 ) ( C E ~)

MF(×10

After 1 month 6)(CE)

1

5.1 (14)

0.5 (15)

2 3 4 5 6 7 8 9 10

2.8 (11) 4.4 (26) 4.3 (18) 0.9 (10) 7.6 (26) 3.2 (3) 3.0 (3) 4.3 (6) 7.2 (15)

4.6 (18) 4.5 (29) 7.7 (10) 3.2 (3) 12.1 (21) 2.7 (3) 9.4 (8) 0.7.(13) 7.6 (38)

11

0.8 (32)

3.3 (39)

Mean,+ SD

4.0-+2.2 (15)

5.1 -+4.5 (18)

12 13 14 15 16 17 18 19 20 21 22 23 24

1.7 (8) 4.8 (3) 2.3 (15) 16.1 (22) 2.1 (43) (/.6 (28) 2.0 (67) 6.3 (6) 15.4 (2) 2.7 (19) 16.5 (12) 0.7 (38) 9.8 (1)

Overall mean + SD (n - 24)

MF(×I0

~)(CE)

4.3 (5) 3.6 (15) 4.6 (13) 3.0 (18) 0.3 (38) 3.0 (15) 0.3 (38) 2.9 (6) 3.7 (4) 1.7 (40) 6.5 (15) 3.1 ,+ 1.8 (19)

1.3 (6) 4.9 (1) 1.8 (19) 20.9 (45) 3.5 (41) 1.1 (39) 2.1 (53) 0.8 (16) 17.2 (2) 0.4 (64) 8.2 (6) 5.9 (16) 12.7 (1)

5.2_+4.8 (18)

5.7+5.4 (21)

;~ CE. cloning efficiency, expressed as a percent.

TABLE 3 1N VIVO hprt MUTANT FRACTION (MF) IN HODGKIN'S DISEASE PATIENTS AFTER X-RAY THERAPY Subject

Age

Months after treatment

CE ~ (%)

MF ( × 1 0 6)

1

57 34 29 48 39 25

77 178 41 240 60 60

18.1 8.2 12.8 23.9 37.3 16.0

19.9 21.8 3.7 29.9 7.6 35.0

19.4!_9.3

19.7+_11.1

2 3 4 5 6 Mean,+ SD

~' CE, cloning efficiency.

b e h i g h l y m u t a g e n i c in h u m a n l y m p h o b l a s t o i d cells. H o w e v e r , w h e n t h e USl is i n t r a c e l l u l a r b u t n o t c o v a l e n t l y b o u n d t o D N A , it e x h i b i t s little c y t o t o x i c i t y a n d is n o t m u t a g e n i c ( W h a l e y a n d L i t t l e , 1990). H e n c e , it a p p e a r s t h a t v e r y l o c a l i z e d n u c l e a r e n e r g y d e p o s i t i o n is a n i m p o r t a n t f a c t o r in t h e p r o d u c t i o n o f b i o l o g i c d a m a g e f r o m A u g e r electron decay. Thus, the current studies suggest t h a t 2°1T1, w h i c h is e x c h a n g e d f o r p o t a s s i u m in t h e cell, is n o t f o u n d in a p p r e c i a b l e c o n c e n t r a t i o n a n d / o r in c l o s e e n o u g h p r o x i m i t y to t h e D N A of l y m p h o c y t e s to y i e l d a s i g n i f i c a n t i n c r e a s e in m u t a n t s a f t e r in v i v o a d m i n i s t r a t i o n o f t h e r a d i o nuclide. W o r k is c u r r e n t l y u n d e r w a y to f u r t h e r in-

245

vestigate the genetic effects of exposure to low doses of radiation from other diagnostic nuclear medicine procedures.

Acknowledgements The authors thank Virginia Braga for help in manuscript preparation and the study participants for their interest in our work. We also thank Dr. Gerald Kolodny for his advice and support. This work was supported by Department of Energy Grant DE-FG02-89ER6074. References Bradley, E.W,, P.C. Chang and S.J. Adelstein (1975) The radiotoxicity of iodine-125 in mammalian cells, Radiat. Res., 64, 555-563. Brandom, W.F., and A.D. Bloom (1983) Progress and topics in cytogenetics, in: T. Ishihara and M.S. Sasaki (Eds.), Radiation-induced Chromosome Damage in Man, Liss, New York, pp. 513 526. Burki, H.J., R. Roots, L.E. Feinendegen and V.P. Bond (1976) Inactivation of mammalian cells after disintegration of 3H or 1251 in cell DNA at - 1 9 6 ° C , Int. J. Radiat. Biol,, 24, 363-373. Caggana, M., H.L. Liber, P.M. Mauch, C.N. Coleman and K.T. Kelsey (1991) In vivo somatic mutation in T-lymphocytes from Hodgkin's disease patients, Environ. Mol. Mutagen., in press. Chan, P.C., E. Lisco, H. Lisco and S.J. Adelstein (1976) The radiotoxicity of iodine-125 in mammalian cells. II. A comparative study on cell survival and cytogenetic responses to 1251UdR, 131TUdR. and 3HTdR, Radiat, Res., 67, 332-343. Chiltom H.M., R.J. Callahan and J.H. Thrall (1990) Radiopharmaceuticals for cardiac imaging: myocardial infarction, perfusiom metabolism, and ventricular function (blood pool), in: D.P. Swanson, H.M. Chilton and J.H. Thrall (Eds.), Pharmaceuticals in Medical Imaging, New York. Davy, D.R. (1969) Symposium on Neutrons in Radiobiology, USAEC, Conf-691106, pp. 451-460. Editorial (1985) Lancet, 32, 533-534. Edwards, A.A., R.J. Purrott, J.S. Prosser and D.C. Lloyd (1980) The induction of chromosome aberrations in human lymphocytes by alpha-radiation. Int. J. Radiat. Biol., 38, 83 91. Evans, H.J., K.E. Buckton, G.E. Hamilton and A. Carothers (1979) Radiation-induced chromosome aberrations in nuclear-dockyard workers, Nature (London), 277, 531-534. Gaulden, M.E. (1983) Biological dosimetry of radionuclides and radiation hazards, J. Nucl. Med., 24, 160-164. Hall, E.J., J.K. Novak. A.M. Kellerer, H.H. Rossi, S. Marino and L.J. Goodman (1975) RBE as a function of neutron energy, Radiat. Res., 64, 245-255. Harbottle, E.A,, R.P. Parker and R. Davis (1976) Radiation

doses to staff in a department of nuclear medicine, Br. J. Radiol., 49, 612-617. Heller, G.V., J.M. Aroesty, J.A. Parker et al. (1984) The pacing stress test: thallium-201 myocardial imaging after atrial pacing. Diagnostic value in detecting coronary artery disease compared with exercise testing, J. Am. Coll. Cardiol.. 3, 1197-1204. Hofer, K.G., and W.L. Hughes (197l) Radiotoxicity of intranuclear tritium, 125 iodine and 131 iodine, Radiat. Res., 47, 94-109. Hofer, K.G., C.R. Harris and J.M. Smith (1975) Radiotoxicity of intraceltular 67Ga, 1251 and 3H. Nuclear versus cytoplasmic radiation effects in murine L1210 leukemia, Int. J. Radiat. Biol., 28, 225-241. lshihara, T., and T. Kumatori (1983) Progress and topics in cytogenetics, in: T. Ishihara and M.S. Sasaki (Eds.), Radiation-induced Chromosome Damage in Man, Liss, New York, pp. 475-490. Kassis, A.I., and S.J. Adelstein (1980) Radiotoxicity of 7~Se and 35S: theory and application to a cellular model, Radiat. Res., 84, 407-425. Kassis, A.I., S.J. Adelstein, C. Haydock and K.S.R. Sastry (1983) Thallium-201: an experimental and a theoretical radiobiological approach to dosimetry, J. Nucl. Med., 24, 1164-1175. Kassis, A.I., K.S.R. Santry and S.J. Adelstein (1985) Intracellular distribution and radiotoxicity of chromium-51 in mammalian cells: Auger-electron dosimetry, J. Nucl. Med., 26, 59-67, Lavu, S., P.P. Reddy and O.S. Reddi (1985) Iodine-125 induced micronuclei and sperm head abnormalities in mice, Int. J. Radiat, Biol., 47, 249-253. LeMotte, P.K., and J.B. Little (1983) A comparison of the lethal effects of intracellular radionuclides in human and rodent cells, Radiat. Res., 95, 359-369. Liber, H.L., P.K. LeMotte and J.B. Little (1983) Toxicity and mutagenicity of X-rays and [1251]dUrd or [3H]TdR incorporated in the DNA of human lymphoblast cells, Mutation Res., 111,387-404. Little, J.B,, P.K. LeMotte and H.L. Liber (1983) Quantitative studies of cytotoxicity, mutagenesis and oncogenic transformation by radioisotopes incorporated into DNA, in: C.C. Harris and H.N. Autrup (Eds.), Human Carcinogenesis, New York, pp. 545 559. Lloyd, D.C., R.J. Purrott and G.W. Dolphin (1973) Chromosome aberration dosimetry using human lymphocytes in simulated partial body irradiation, Phys. Med. Biol., 18, 421-431. Makrigiorgos, G.M., S.J. Adelstein and A.I. Kassis (1989) Limitations of conventional internal dosimetry at the cellular level, J. Nucl. Med., 30, 1856-1864. Merz, T., J. Tatum and J. Hirsch (1986) Technetium-99mlabeled lymphocytes: a radiotoxicity study, J. Nucl. Med., 27, 105-110. Messing, K., and W.E.C. Bradley (1985) In vivo mutant frequency rises among breast cancer patients after exposure to high doses of gamma-radiation, Mutation Res., 152, 107-112.

246 O'Neill, J.P., L.M. Sullivan and R.J. Albertini (1990) In vitro induction, expression and selection of thioguanine-resistant mutants with human T-lymphocytes, Mutation Res., 240, 135-142. Pohl-Ruling, J., and P. Fischer (1983) Progress and topics in cytogenetics, in: T. Ishihara and M.S. Sasaki (Eds.), Radiation-induced Chromosome Damage in Man, Liss, New York, pp. 527-560. Rao, D.V., G.F. Govelitz and K.S.R. Sastry (1983) Radiotoxicity of thallium-201 in mouse testes: inadequacy of conventional dosimetry, J. Nucl. Med., 24, 145-153. Roberts, C.J., and P.D. Holt (1982) The production of chromosome aberrations in Chinese hamster fibroblasts by gamma and neutron radiation, Int. J. Radiat. Biol., 41, 645-656. Roberts, C.J., G.R. Morgan and P.D. Holt (1987) The production of chromosome aberration in Chinese hamster fibroblasts exposed to 24 keV neutrons, Int. J. Radiat. Biol., 51, 341-351. Seifert, A.M., W.E.C. Bradley and K. Messing (1987) Exposure of nuclear medium patients to ionizing radiation is associated with risk in HPRT mutant frequency in peripheral T-lymphocytes, Mutation Res., 191, 57-63.

Tawn, E.J., J.W. Hall and G.B. Schofield (1985) Chromosome studies in plutonium workers, Int. J. Radiat. Biol., 4"7, 599-610. Ten Berge, R.J.M., A.T. Natarajan, M.R. Hardeman, E.A. van Royen and P.T.A. Schellekens (1983) Labeling with ind i u m - I l l has detrimental effects on human lymphocytes: concise communication, J. Nucl. Med., 24, 615 620. Thakur, M.L., and J.G. McAfee (1984) The significance of chromosomal aberrations in indium-l 1 l-labeled lymphocytes, Int. J. Nucl. Med., 25,922-92"7. Vijayalaxmi, and H.J. Evans (1984) Measurement of spontaneous and X-irradiation-induced 6-thioguanine-resistant human blood lymphocytes using a T-cell cloning technique, Mutation Res., 125, 87-94. Wafters, R.L., K.G. Hofer and C.R. Harris (1978) Radionuclide toxicity in cultured mammalian cells: elucidation of the primary site of radiation damage, Curr. Top. Radiat. Res., 93, 112-146. Whaley, J.M., and J.B. Little (1990) Efficient mutation induction by 125I and 1311 decays into DNA of human cells, Radiat. Res., in press.

Genotoxic and mutagenic effects of the diagnostic use of thallium-201 in nuclear medicine.

In order to investigate possible mutagenic effects of in vivo exposure to low levels of ionizing radiation used in nuclear medicine, we have examined ...
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