Radiation dose and second cancer risk in patients treated for cancer of the cervix

The risk of cancer associated with a broad range of organ doses was estimated in an international study of women with cervical cancer. Among 150,000 patients reported to one of 19 population-based cancer registries or treated in any of 20 oncology clinics, 4188 women with second cancers and 6880 matched controls were selected for detailed study. Radiation doses for selected organs were reconstructed for each patient on the basis of her original radiotherapy records. Very high doses, on the order of several hundred gray, were found to increase the risk of cancers of the bladder [relative risk (RR) = 4.0], rectum (RR = 1.8), vagina (RR = 2.7), and possibly bone (RR = 1.3), uterine corpus (RR = 1.3), cecum (RR = 1.5), and non-Hodgkin's lymphoma (RR = 2.5). For all female genital cancers taken together, a sharp dose-response gradient was observed, reaching fivefold for doses more than 150 Gy. Several gray increased the risk of stomach cancer (RR = 2.1) and leukemia (RR = 2.0). Although cancer of the pancreas was elevated, there was no evidence of a dose-dependent risk. Cancer of the kidney was significantly increased among 15-year survivors. A nonsignificant twofold risk of radiogenic thyroid cancer was observed following an average dose of only 0.11 Gy. Breast cancer was not increased overall, despite an average dose of 0.31 Gy and 953 cases available for evaluation (RR = 0.9); there was, however, a weak suggestion of a dose response among women whose ovaries had been surgically removed. Doses greater than 6 Gy to the ovaries reduced breast cancer risk by 44%. A significant deficit of ovarian cancer was observed within 5 years of radiotherapy; in contrast, a dose response was suggested among 10-year survivors. Radiation was not found to increase the overall risk of cancers of the small intestine, colon, ovary, vulva, connective tissue, breast, Hodgkin's disease, multiple myeloma, or chronic lymphocytic leukemia. For most cancers associated with radiation, risks were highest among long-term survivors and appeared concentrated among women irradiated at relatively younger ages.     

Induction of chromosome aberrations and micronuclei in human peripheral blood lymphocytes at low dose of radiation

The chromosome damage induced by the doses of y-irradiation 6)Co in peripheral blood lymphocytes was studied using different cytogenetic assays. Isolated lymphocytes were exposed to 0.01-1.0 Gy, stimulated by PHA, and analysed for chromosome aberrations at 48 h postirradiation by metaphase method, at 49 h--by the anaphase method, at 58 h by micronucleus assay with cytochalasin B and, additionally, micronuclei were counted at 48 h on the slides prepared for the metaphase analysis without cytochalasin B. Despite of the quantitative differences in the amount of chromosome damage revealed by different methods all of them demonstrated complex nonlinear dose dependence of the frequency of aberrant cells and aberrations. At the dose range from 0.01 Gy to 0.05-0.07 Gy the cells had the highest radiosensitivity mainly due to chromatid-type aberration induction. With dose increasing the frequency of the aberrant cells and aberrations decreased significantly (in some cases to the control level). At the doses up to 0.5-0.7 Gy the dose-effect curves have become linear with the decreased slope compare to initial one (by factor of 5 to 10 for different criteria) reflecting the higher radioresistance of cells. These data confirm the idea that the direct linear extrapolation of high dose effect to low dose range--the procedure routinelly used to estimate genetic risk of low dose irradiation--cannot be effective and may lead to underestimation of chromosome damage produced by low radiation doses. Preferences and disadvantages of used cytogenetic assays and possible mechanisms of low ionising radiation doses action were discussed.     

Chromosomal aberrations in peripheral lymphocytes of patients treated with radium-224 for ankylosing spondylitis

The aim of this study was to investigate the in vivo frequency of chromosomal aberrations (primarily dicentric chromosomes and chromatid breaks) potentially induced by ²²⁴Ra -radiation in peripheral lymphocytes. The study was designed to serve as a cytogenetic analysis along with the therapeutic procedure of ankylosing spondylitis patients who were undergoing a treatment with ²²⁴Ra-chloride. The total administered activity was 10 MBq, and the treatment followed a schedule of 10 i.v. injections per week, each with a dose of 1 MBq of ²²⁴Ra. The calculation of absorbed doses delivered to the blood used the models suggested by the ICRP and yielded a value of 4.7 mGy/MBq. The frequency of chromosomal aberrations observed during the course of therapy was related to the blood dose. The frequency of dicentric chromosomes induced in vivo was found to agree well with the corresponding value of dicentrics induced in vitro. However—given that peripheral lymphocytes are in the cell cycles G₀ stage—an unexpected increase with dose in the yield of chromatid breaks was observed, with about 95% of them occurring in cells without any other chromosome-type aberrations. Reasons for the production of chromatid breaks are discussed.     

Chromosome aberrations in relation to radiation dose following partial-body exposures in three populations

Structural chromosome aberrations were evaluated in peripheral blood samples obtained from three populations exposed to partial-body irradiation. These included 143 persons who received radiotherapy for enlarged thymus glands during infancy and 50 sibling controls; 79 persons irradiated for enlarged tonsils and 81 persons surgically treated for the same condition during childhood; and 77 women frequently exposed as young adults to fluoroscopic chest X rays during lung collapse treatment for tuberculosis (TB) and 66 women of similar ages treated for TB with other therapies. Radiation exposures occurred 30 and more years before blood was drawn. Doses to active bone marrow averaged over the entire body were 21, 6, and 14 cGy for the exposed thymic, tonsil, and TB subjects, respectively. Two hundred metaphases were scored for each subject, and the frequencies of symmetrical (stable) and asymmetrical (unstable) chromosome aberrations were quantified in 97,200 metaphases. Cells with stable aberrations were detected with greater frequency in the irradiated subjects compared with nonirradiated subjects in all three populations, and an overall test for an association between stable aberrations and partial-body ionizing radiation was highly significant (P less than 0.001). We found no evidence that radiation-induced aberrations varied by age at exposure. These data show that exposure of children or young adults to partial-body fractionated radiation can result in detectable increased frequencies of stable chromosome aberrations in circulating lymphocytes 30 years later, and that these aberrations appear to be informative as biological markers of population exposure.     

Chromosome aberrations in peripheral blood lymphocytes of individuals living in high background radiation areas of Ramsar,Iran

In order to investigate the biological effects of exposure to low-dose radiation and to assess the dose–effect relationship in residents of high background radiation areas (HBRAs) of Ramsar, cytogenetic investigation of unstable-type aberrations was performed in 15 healthy elderly women in a HBRA of Ramsar, Talesh mahalle, and in 10 elderly women living in a nearby control area with normal background radiation. In total, 77,714 cells were analyzed; 48,819 cells in HBRA residents and 28,895 cells in controls. On average, 3,108 cells per subject were analyzed (range 1,475–5,007 cells). Significant differences were found in the frequency of dicentric plus centric rings in 100 cells (0.207 ± 0.103 vs. 0.047 ± 0.027, p < 0.0005), total chromosome-type aberrations per 100 cells (0.86 ± 0.44 vs. 0.23 ± 0.17, p < 0.0005), and chromatid-type aberrations per 100 cells (3.31 ± 2.01 vs. 1.66 ± 0.63, p = 0.01) by the Mann–Whitney U test between HBRA and the control, respectively. Using chromosomal aberrations as the main endpoint to assess the dose–effect relationship in residents of HBRAs in Ramsar, no positive correlation was found between the frequency of dicentric plus centric ring aberrations and the cumulative dose of the inhabitants estimated by direct individual dosimetry; however, obvious trends of increase with age appeared in the control group. Based on these results, individuals residing in HBRAs of Ramsar have an increased frequency of detectable abnormalities in unstable aberrations.     

Chromosome aberrations and sister-chromatid exchanges (SCEs) in peripheral blood lymphocytes of patients suffering from poliomyelitis

The frequencies of sister-chromatid exchanges (SCEs) and various chromosome aberrations were studied in blood lymphocyte cultures of individuals suffering from polio virus infection. The frequency of SCEs was found to be within the normal range in polio patients whereas the frequency of chromatid breaks, gaps and other chromosome aberrations showed a significant (p less than 0.001) increase when compared with that of controls. It indicates that the mechanism(s) responsible for polio virus-induced chromosomal damage may not be related to or affect the molecular process(es) that functions in SCE formation.     

Chromosome aberrations induced in human lymphocytes by radiation from 252Cf.

In vitro dose--response curves of unstable chromosome aberrations in human lymphocytes have been obtained for 252Cf neutron radiation. The aberration yields fitted best to the linear function Y=aD, which is consistent with the single-track model of aberration formation for high LET radiation. The curves have been compared with others previously produced in this laboratory for several energies of neutrons and for 60Co gamma radiation. The r.b.e. for 252Cf with respect to 60Co is 27 at very low doses, decreasing to 6 at an aberration yield equivalent to 400 rad of 18 rad/hour gamma radiation. A profile of chromosome-aberration induction with depth in a perspex phantom was obtained by placing blood samples at several distances over the range 0.65-2.0 cm from the californium source. This profile was compared with depth-damage calculations for a radium needle. The r.b.e. of 252Cf radiation relative to 226Ra gamma radiation increased with the distance from the source, implying that californium is more effective at greater distances in destroying the ability of cells to divide, which may be an advantage in the treatment of large tumours.     

Chromosomal damage in peripheral blood lymphocytes of patients treated for testicular cancer

Summary We describe the presence of a large number of chromosome aberrations in lymphocytes of 50 patients with testicular cancer. These chromosomal aberrations were not only found in patients treated with chemotherapy but also in untreated patients or in patients after surgery alone. Our results suggest a role for genetic instability in the pathogenesis of testicular cancer. This instability might be a risk factor for the development of secondary malignancies.     

Time-effect relationship of chromosome aberrations in peripheral lymphocytes after radiation therapy for seminoma

The time-effect relationship of dicentrics and cells containing unstable chromosome abnormalities (Cu cells) was studied in peripheral lymphocytes of 40 blood samples from 23 patients suffering from seminoma during a time period of 0-1720 days after radiation therapy. Nine patients were studied before treatment. Since the half-time for the disappearance of damaged cells from circulating blood is an increasing function of post-exposure time it can only be expressed as a differential value. The present model discriminates between the mean lifetime m for lymphocytes and a parameter q which is the differential half-time for the decline of damaged cells immediately after exposure (t = 0). If the time t is short compared with m the decline is asymptotically time-hyperbolic rather than exponential and can be described by q only. According to recalculations of previous data, comprising 30 years post exposure, m approximates 10 years. Differential half-times can be derived for any time post treatment within the analysed time period for the decline of the incidence of dicentrics. For example at the end of therapy (t = 0) the differential half-time was calculated to be 0.4 years and at 1720 days post exposure 3.6 years resulted. The corresponding values for the percentage of Cu cells cannot be derived for t = 0; at 1720 days 3.9 years resulted.     

Chromosome aberrations do not persist in the lymphocytes or bone marrow cells of mice irradiated in utero or soon after birth

Mice were exposed at various ages to 1 Gy or 2 Gy of X rays, and translocation frequencies in peripheral blood T cells, spleen cells, and bone marrow cells were determined with FISH painting of chromosomes 1 and 3 when the animals were 20 weeks old. It was found that the mean translocation frequencies were very low (< or =0.8%) in mice exposed in the fetal or early postnatal stages. However, with the increase in animal age at the time of irradiation, the frequency observed at 20 weeks old became progressively higher then reached a plateau (about 5%) when mice were irradiated when > or =6 weeks old. A major role of p53 (Trp53)-dependent apoptosis for elimination of aberrant cells was not suggested because irradiated fetuses, regardless of the p53 gene status, showed low translocation frequencies (1.8% in p53(-/-) mice and 1.4% in p53(+/-) mice) compared to the frequency in the p53(-/-) mother (7.4%). In contrast, various types of aberrations were seen in spleen and liver cells when neonates were examined shortly after irradiation, similar to what was observed in bone marrow cells after irradiation in adults. We interpreted the results as indicating that fetal cells are generally sensitive to induction of chromosome aberrations but that the aberrant cells do not persist because fetal stem cells tend to be free of aberrations and their progeny replace the pre-existing cell populations during the postnatal growth of the animals.     

Chromosome aberrations induced by monomeric acrylamide in bone marrow and germ cells of mice

Acrylamide induces chromatid exchanges and breaks with considerable frequency in spermatogonia of mice with long-term administration (3 weeks), though not, remarkably, with short-term administration (1–2 weeks). At 12 and 24 h after single injections with 50, 100 and 150 mg/kg acrylamide, evaluation of the cytogenetic effect is difficult in the spermatogonia because of an extreme reduction of mitotic cells. Aneuploid and polyploid cells increase with ti,e after treatment in both marrow and spermatogonial cells, while the aberration frequency shows no increase in marrow after both oral-administration and injection. Evidently the spermatogonia are thus rather more sensitive to acrylamide than marrow cells. On the other hand, the SCE frequency is at the control level in treated subjects in marrow and spermatogonia. Acrylamide induces chain quadrivalents, ring quadrivalents, fragments and univalents which are particularly evident in primary spermatocytes in both oral administration and injection, though it is questionable whether these structural changes deal with spermatogonia, or otherwise with the S-phase primary spermatocytes. There is a possibility that the aberrant cells thus produced can develop into spermatozoa carrying a certain type of reciprocal translocation which leads to semi-sterile progeny. In relation to the above problem detailed investigations into this type of rearrangement in primary spermatocytes are needed.     

Chromosomal aberrations in bone marrow and peripheral blood cells from the same rats

Spontaneous cytogenetic aberrations were analyzed in bone-marrow cells and cultured peripheral lymphocytes from the same animals. No significant differences in the total number of cells with aberrations or total aberrations were detected between the bone-marrow cells and cultured lymphocytes. It was concluded that short-term culture does not contribute significantly to in vivo aberration yield within the experimental conditions used.     

Chromosome aberrations in lymphocytes after occupational exposure to lead and cadmium

Chromosomes were analysed in peripheral lymphocytes of 24 workers in a zinc smelting plant who had increased blood levels of lead and cadmium. The number of cells with structural chromosome aberrations was significantly increased as compared with 15 controls. The observed chromosome damage was mainly of the chromatid type (single breaks and exchanges) accompanied by acentric fragments. The observed chromosome aberrations cannot be causally related to cadmium because the workers were additionally exposed to lead and zinc. However, from existing cytogenetic data on heavy metals an effect of cadmium could be well deduced, although possible synergistic effects of several metal compounds, especially under conditions, in vivo, cannot be excluded.     

Chromosome aberrations, sister-chromatid exchanges and cell-cycle kinetics in human peripheral blood lymphocytes exposed to organoselenium in vitro

The ability of 2 synthetic organoselenium compounds, a dimer of p-methoxybenzeneselenol (DPMBS) and benzylselenocyanate (BSC), to induce sister-chromatid exchanges (SCE) and chromosome aberrations (CA) as well as to alter the progression of the cell through mitosis has been investigated in cultured human lymphocytes. Cultures treated with the highest concentration (2.27 x 10(-5) M) of the 2 compounds exhibited about a 3-fold increase in the level of SCE and about 2-3-fold increase in the incidence of CA. In addition, the 2 selenium compounds led to an inhibition of cell proliferation as was evidenced by the depression of the proliferation rate index (PRI).     

Chromosome aberration frequency and radiation dose to lymphocytes by alpha-particles from internal deposit of Thorotrast

Summary Frequencies of chromosome aberrations in peripheral blood lymphocytes from 63 Thorotrast patients were analysed basing on the age distribution of lymphocytes. The frequency and distribution of chromosome aberrations among lymphocytes are best explained if we assume that the lymphocytes are renewed as an exponential function of time and spend most of their lifetime in the distributive pool where, while exchange of lymphocytes is taking place, the lymphocytes are hit by-particles from Thorotrast aggregates resulting in the formation of chromosome aberrations and killing at specific rates per hit. The model predicts that the aberration frequency is rather insensitive to the fluence rate because of modulation by cell killing by hit. Fitting the observed data to the model showed that approximately 0.8 dicentrics and rings were produced by a single path of-particle and average fluence rate to lymphocytes in a group of patients with the highest aberration frequency was estimated to be about 1.5 hits or 87 rad/lymphocyte/year.     

Radiation-induced chromosomal aberrations in the bone marrow of mice exposed to various doses of gamma radiation

The occurrence of chromosomal aberrations was studied at 1–14 days post-exposure in female BALB/c mice exposed to various doses of gamma radiation. The frequency of abnormal cells, chromatid and chromosome breaks, dicentrics, centric rings, acentric fragments and total aberrations increased with exposure dose, and it was highest at 7 Gy. A peak was recorded on day 1 post-exposure with a gradual decline thereafter. The chromosomal aberration yield reached a nadir on day 14 post-irradiation, without restoration to the control level. The best fit for the present data was by a linear-quadratic relationship between dose of radiation and the frequency of chromosomal aberrations.     

Chromosomal aberrations in peripheral lymphocytes of alcoholics

The frequencies of exchange-type aberrations found in peripheral lymphocytes of alcoholics were analysed in relation to age, sex, duration of alcohol dependency, treatment with antabuse and smoking habit. The statistical analyses were performed by the non-parametric Mann-Whitney U test and the Kruskal-Wallis 1-way analysis of vairance, both at a level of significance of P = 0.05. There was no dependency on age or sex. The chromatid exchange frequencies and the total of all exchanges were positively correlated with the duration of the dependency on alcohol and with smoking habit. Treatment with antabuse did not lead to an additional elevation of the frequency of exchange-type aberrations.     

Induction of chromatid-type aberrations in peripheral lymphocytes of hospital workers exposed to very low doses of radiation

Radiological personnel represent workers exposed to low cumulative doses of radiation. As their surveillance is generally based on physical dosimetry, there is little or inconclusive information on biological effects due to radiation exposure at these doses. We aimed to explore the extent of chromosomal damage in circulating lymphocytes of hospital workers (technicians, nurses and physicians) chronically exposed to a very low level of radiation using conventional and molecular cytogenetic analyses (chromosome painting with chromosomes #2, #3 and #10 as probe cocktail). Compared with controls, exposed workers displayed a significant increase in the frequency of aberrant lymphocytes (1.26+/-0.11/100 cells versus 1.63+/-0.17/100 cells). In particular, exposed technicians showed significantly higher mean values than nurses or physicians (3.68+/-1.17/100 cells versus 1.36+/-0.18/100 cells and 1.36+/-0.09/100 cells, respectively). Interestingly, we found that the chromosomal damage was prevalently expressed as chromatid-type aberrations. Chromosome painting indicated that the frequency of chromosome rearrangements (CR; translocations and dicentrics pooled together) was approximately comparable between radiological workers and the control group. Moreover, we did not detect any significant difference due to radiation exposure when CR rates were considered separately for each of the three chromosomes in the probe cocktail.