Linear-quadratic Dose-response Model Research Articles

Predictions of cognitive detriments from galactic cosmic ray exposures to astronauts on exploration missions

For the first-time we report on predictions on cognitive detriments from galactic cosmic ray (GCR) exposures on long-duration space missions outside the protection of the Earth's magnetosphere and solid body shielding. Estimates are based on a relative risk (RR) model of the fluence response for proton and heavy ion in rodent studies using the widely used novel object recognition (NOR) test, which estimates detriments in recognition or object memory. Our recent meta-analysis showed that linear and linear-quadratic dose response models were not accurate, while exponential increasing fluence response models based on particle track structure provided good descriptions of rodent data for doses up to 1 Gy. Using detailed models of the GCR environment and particle transport in shielding and tissue, we predict the excess relative risk (ERR) for NOR detriments for several long-term space mission scenarios. Predictions suggest ERR < 0.15 for most space mission scenarios with ERR<0.1 for 1-year lunar surface missions, and about ERR~0.1 for a 1000 day Mars mission for average solar cycle conditions. We discuss possible implications of these ERR levels of cognitive performance detriments relative to other neurological challenges such as rodent models of Alzheimer's disease (AD), Parkinson's disease (PD) and traumatic brain injury (TBI). Comparisons suggest a small but potentially clinically significant risk for possible space mission scenarios.

Meta-analysis of Cognitive Performance by Novel Object Recognition after Proton and Heavy Ion Exposures.

Experimental studies of cognitive detriments in mice and rats after proton and heavy ion exposures have been performed by several laboratories to investigate possible risks to astronauts exposed to cosmic rays in space travel and patients treated for brain cancers with proton and carbon beams in Hadron therapy. However, distinct radiation types and doses, cognitive tests and rodent models have been used by different laboratories, while few studies have considered detailed dose-response characterizations, including estimates of relative biological effectiveness (RBE). Here we report on the first quantitative meta-analysis of the dose response for proton and heavy ion rodent studies of the widely used novel object recognition (NOR) test, which estimates detriments in recognition or object memory. Our study reveals that linear or linear-quadratic dose-response models of relative risk (RR) do not provide accurate descriptions. However, good descriptions for doses up to 1 Gy are provided by exponentially increasing fluence or dose-response models observed with an LET dependence similar to a classical radiation quality response, which peaks near 100-120 keV/µm and declines at higher LET values. Exponential models provide accurate predictions of experimental results for NOR in mice after mixed-beam exposures of protons and 56Fe, and protons, 16O and 28Si. RBE estimates are limited by available X-ray or gamma-ray experiments to serve as a reference radiation. RBE estimates based on use of data from combined gamma-ray and high-energy protons of low-LET experiments suggest modest RBEs, with values <8 for most heavy ions, while higher values <20 are based on limited gamma-ray data. In addition, we consider a log-normal model for the variation of subject responses at defined dose levels. The log-normal model predicts a heavy ion dose threshold of approximately 0.01 Gy for NOR-related cognitive detriments.

TOWARDS THE USE OF NANODOSIMETRY TO PREDICT CELL SURVIVAL.

Experimental nanodosimetry aims to develop a new concept of radiation quality, based on the correlation between initial features of particle tracks and late biological outcome. A direct proportionality has been observed between the cumulative probability of measuring at least k ionisations within a nanometric volume and inactivation cross sections at specific survival levels. Based on this proportionality, physical quantities which are measurable at the nanometre level can be used to estimate the alpha and beta parameters of the linear-quadratic dose-response model, provided that two proportionality factors are determined in a reference radiation field. This work describes the procedure and first results applied to published data for V79 cell survival after irradiation with protons and carbon ions.

Transcriptome-based biological dosimetry of gamma radiation in Arabidopsis using DNA damage response genes

Plants are used as representative reference biota for the biological assessment of environmental risks such as ionizing radiation due to their immobility. This study proposed a faster, more economical, and more effective method than conventional cytogenetic methods for the biological dosimetry of ionizing radiation in plants (phytodosimetry). We compared various dose-response curves for the radiation-induced DNA damage response (DDR) in Arabidopsis thaliana after relatively “low-dose” gamma irradiation (3, 6, 12, 24, and 48 Gy) below tens of Gy using comet (or single-cell gel electrophoresis), gamma-H2AX, and transcriptomic assays of seven DDR genes (AGO2, BRCA1, GRG, PARP1, RAD17, RAD51, and RPA1E) using quantitative real time PCR. The DDR signal from the comet assay was saturated at 6 Gy, while the gamma-H2AX signal increased up to 48 Gy, following a linear-quadratic dose-response model. The transcriptional changes in the seven DDR genes were fitted to linear or supra-linear quadratic equations with significant dose-dependency. The dose-dependent transcriptional changes were maintained similarly until 24 h after irradiation. The integrated transcriptional dose-response model of AGO2, BRCA1, GRG, and PARP1 was very similar to that of gamma-H2AX, while the transcriptional changes in the BRCA1, GRG, and PARP1 DDR genes revealed significant dependency on the dose-rate, ecotype, and radiation dose. These results suggest that the transcriptome-based dose-response model fitted to a quadratic equation could be used practically for phytodosimetry instead of conventional cytogenetic models, such as the comet and gamma-H2AX assays. The effects of dose-rate and ecotype on the transcriptional changes of DDR genes should also be considered to improve the transcriptome-based phytodosimetry model.

Robust spatiotemporally integrated fractionation in radiotherapy

Spatiotemporally integrated fractionation involves finding a fluence-map and a number of treatment sessions that maximize tumor-kill subject to dose-limits on organs-at-risk (OAR). This problem was recently formulated using the linear–quadratic dose–response model. Owing to the uncertainty in dose–response parameters, however, a solution presumed optimal might be infeasible in practice. We address this via a robust counterpart and its convex reformulation wherein the price of robustness is small and robust solutions are less infeasible than nominal even outside our uncertainty sets.

The Increase in Animal Mortality Risk following Exposure to Sparsely Ionizing Radiation Is Not Linear Quadratic with Dose.

IntroductionThe US government regulates allowable radiation exposures relying, in large part, on the seventh report from the committee to estimate the Biological Effect of Ionizing Radiation (BEIR VII), which estimated that most contemporary exposures- protracted or low-dose, carry 1.5 fold less risk of carcinogenesis and mortality per Gy than acute exposures of atomic bomb survivors. This correction is known as the dose and dose rate effectiveness factor for the life span study of atomic bomb survivors (DDREFLSS). It was calculated by applying a linear-quadratic dose response model to data from Japanese atomic bomb survivors and a limited number of animal studies.Methods and ResultsWe argue that the linear-quadratic model does not provide appropriate support to estimate the risk of contemporary exposures. In this work, we re-estimated DDREFLSS using 15 animal studies that were not included in BEIR VII’s original analysis. Acute exposure data led to a DDREFLSS estimate from 0.9 to 3.0. By contrast, data that included both acute and protracted exposures led to a DDREFLSS estimate from 4.8 to infinity. These two estimates are significantly different, violating the assumptions of the linear-quadratic model, which predicts that DDREFLSS values calculated in either way should be the same.ConclusionsTherefore, we propose that future estimates of the risk of protracted exposures should be based on direct comparisons of data from acute and protracted exposures, rather than from extrapolations from a linear-quadratic model. The risk of low dose exposures may be extrapolated from these protracted estimates, though we encourage ongoing debate as to whether this is the most valid approach. We also encourage efforts to enlarge the datasets used to estimate the risk of protracted exposures by including both human and animal data, carcinogenesis outcomes, a wider range of exposures, and by making more radiobiology data publicly accessible. We believe that these steps will contribute to better estimates of the risks of contemporary radiation exposures.

A tumor control probability model for anal squamous cell carcinoma

Background and purposeA recent update of the RTOG 9811, reported differing relapse rates for early and late anal squamous cell carcinoma following chemoradiotherapy (CRT). There may be a role for dose-individualization, however the dose–response relationship for anal cancer is not currently known.Intensity-modulated radiotherapy (IMRT) has been widely adopted with multiple series published. The aim is to fit a tumor control probability (TCP) model to the published IMRT data. Materials and methodsWe performed a systematic review of PubMed and Embase databases to identify thirteen appropriate papers, including 625 patients. Predefined data fields were collected. A standard linear quadratic TCP model, which included repopulation, was fit by least squares minimization. ResultsThe fitted TCP curve demonstrated a dose–response relationship with α=0.196Gy–1. The curve suggests: in early stage tumours, a dose reduction from 50Gy to 45Gy reduces 2year local control from 98% to 95%; in late stage tumours, a dose escalation from 50Gy to 55Gy improves the 2year local control rate from approximately 50% to 80%. ConclusionsThe published data are broadly consistent with a linear quadratic dose–response model. Dose-individualization in anal cancer should be further investigated in the context of clinical trials.

A two-variable linear program solves the standard linear–quadratic formulation of the fractionation problem in cancer radiotherapy

The standard formulation of the fractionation problem with multiple organs-at-risk based on the linear–quadratic dose–response model requires the solution of a nonconvex quadratically constrained quadratic program. Existing literature therefore uses heuristic methods without any analyses about solution quality. There is no known method that is guaranteed to find an optimal solution. We prove that this formulation of the fractionation problem can in fact be solved to optimality by instead solving a two-variable linear program with a few constraints.

Cataracts among Chernobyl Clean-up Workers: Implications Regarding Permissible Eye Exposures

The eyes of a prospective cohort of 8,607 Chernobyl clean-up workers (liquidators) were assessed for cataract at 12 and 14 years after exposure. The prevalence of strictly age-related cataracts was low, as expected (only 3.9% had nuclear cataracts at either examination), since 90% of the cohort was younger than 55 years of age at first examination. However, posterior subcapsular or cortical cataracts characteristic of radiation exposure were present in 25% of the subjects. The data for Stage 1 cataracts, and specifically for posterior subcapsular cataracts, revealed a significant dose response. When various cataract end points were analyzed for dose thresholds, the confidence intervals all excluded values greater than 700 mGy. Linear-quadratic dose-response models yielded mostly linear associations, with weak evidence of upward curvature. The findings do not support the ICRP 60 risk guideline assumption of a 5-Gy threshold for "detectable opacities" from protracted exposures but rather point to a dose-effect threshold of under 1 Gy. Thus, given that cataract is the dose-limiting ocular pathology in current eye risk guidelines, revision of the allowable exposure of the human visual system to ionizing radiation should be considered.

MEASUREMENT OF MUTANT FREQUENCY IN T-CELL RECEPTOR (TCR) GENE BY FLOW CYTOMETRY AFTER X-IRRADIATION ON EL-4 MICE LYMPHOMA CELLS

It is well known that somatic mutations are induced by ionizing irradiation. We have previously reported the measurement of mutant frequency (MF) on the T-cell receptor (TCR) gene in mouse T-lymphocytes after irradiation by flow cytometry. In this study, we developed an in vitro system using murine EL-4 lymphoma cells and observed frequency of cells defective in TCR gene expression after exposure to ionizing irradiation. EL-4 cells were stained with fluorescein-labeled anti-CD4 and phycoerythrin-labeled anti-CD3 antibodies. They were analyzed with a flow cytometer to detect mutant EL-4 cells lacking surface expression of TCR/CD3 complexes which showed CD3-, CD4+ due to a somatic mutation at the TCR genes. Mutant cells could be observed at 2 days after 3 Gy irradiation. MF of EL-4 cells was 6.7x10(-4) for 0 Gy and the value increased to the maximum level of 39x10(-4) between 4 and 8 days after 3 Gy irradiation and these data were found to be best fitted by a linear-quadratic dose-response model. After the peak value the TCR MF gradually decreased with a half-life of approximately 3.2 days. We also examined the hprt mutant frequencies at seven days after irradiation and the cytokinesis-blocked micronucleus frequency at 20 hrs after irradiation. The frequencies of hprt mutation and micronuclei were found to be best fitted by a linear-quadratic dose-response model and a linear dose-response model, respectively. The method to detect mutation on TCR gene is quick and easy in comparison with other methods and is considered useful for the mutagenicity test.

Micronuclei induced by low dose rate irradiation in early spermatids of p53 null and wild mice.

To obtain evidence of the dose-rate effect on induction of micronuclei in early spermatids, we observed frequencies in wild-type p53(+/+), heterozygous p53(+/-) and null p53(-/-) mice 14 days after gamma rays irradiation at a high (1,020 mGy/min) or a low (1.2 mGy/min) dose-rate. A dose- and dose-rate-related increase in micronuclei was seen in early spermatids with no difference between the different p53 status. These data were found to be best fitted by a linear-quadratic dose-response model at a high dose-rate, and by a linear dose-response model at a low dose-rate. The yields at 1.2 mGy/min were significantly lower than those at 1,020 mGy/min in the same manner, independent of p53 status. Testis weight declined significantly after 3 Gy irradiation, but did not depend on dose-rates. In our other studies, we observed the complete elimination both of malformation in fetuses and CD3- 4+ mutant T-lymphocytes in p53(+/+) mice, but not in p53(-/-) mice after irradiation. This indicates that concerted DNA repair and p53-dependent apoptosis are likely to completely eliminate mutagenic damage from the irradiated tissues at low doses or dose-rates in teratogenesis and lymphocytes. In the germ cell, however, irradiation at 1.2 mGy/min was mutagenic, independent of p53 status.

Stimulated rapid expression in vitro for early detection of in vivo T-cell receptor mutations induced by radiation exposure

The T-cell receptor (TCR) mutation assay for in vivo somatic mutations is a sensitive indicator of exposure to ionizing radiation. However, this assay cannot be immediately applied after radiation exposure because expression of a mutant phenotype may require as long as several months. In the present study, we eliminate this time lag by stimulating lymphocytes with a mitogen that can accelerate the turnover of TCR protein expression in T-cells. When lymphocytes obtained from healthy donors were irradiated with various doses of X-rays and cultured with human interleukin-2 after phytohemagglutinin (PHA) pulse stimulation, the mutant frequency (MF) of CD4 + T-cells increased dose dependently during the first 7 days, then decreased rapidly due to the growth disadvantage of mutant cells. This suggests that PHA stimulation can shorten the expression time of a mutant phenotype to within a week after radiation exposure. The relationship between radiation dose and TCR MF on the seventh day was best fitted by a linear-quadratic dose–response model. We applied this improved TCR mutation assay to gynecological cancer patients who received 5 days of localized radiotherapy, totaling about 10 Gy. The in vivo TCR MF in the patients did not change within a week after radiotherapy, whereas the in vitro TCR MF of PHA-stimulated lymphocytes from the same patients significantly increased 7 days after initiating culture. The estimated mean radiation dose to the peripheral blood lymphocytes of the cancer patients was about 0.9 Gy, based on the in vitro linear-quadratic dose–response curve. This estimated dose was close to that described in a previous report on unstable-type chromosome aberrations from cervical cancer patients after receiving the same course of radiotherapy. On the basis of these findings, we propose that the improved TCR mutation assay is a useful biological dosimeter for recent radiation exposure.

A two-mutation model of radiation carcinogenesis: application to lung tumours in rodents and implications for risk evaluation

An attempt is made to develop a model for radiation carcinogenesis linking DNA damage to malignancy. A modification of the two-stage model for carcinogenesis developed by Knudson and Moolgavkar (see J. Natl. Acad. Sci. (USA), vol. 68, p. 1037-52, 1981) is combined with a linear-quadratic dose response model for cellular radiation effects to analyse radiation induced lung tumours in rodents for a variety of radiation types and conditions. The combined model provides the possibility of calculating the age dependent and dose dependent incidence of cancer simultaneously and is used to fit data of lung tumours in mice and rats exposed to different radiation types. The satisfactory application of the combined model to animal data has led to an examination of the implications of the model, which may prove to be far-reaching for the extrapolation of risk to low doses, the effect of life exposures and other aspects of radiation risk assessment.

Cancer Incidence in Atomic Bomb Survivors. Part II: Solid Tumors, 1958-1987

This report presents, for the first time, comprehensive data on the incidence of solid cancer and risk estimates for A-bomb survivors in the extended Life Span Study (LSS-E85) cohort. Among 79,972 individuals, 8613 first primary solid cancers were diagnosed between 1958 and 1987. As part of the standard registration process of the Hiroshima and Nagasaki tumor registries, cancer cases occurring among members of the LSS-E85 cohort were identified using a computer linkage system supplemented by manual searches. Special efforts were made to ensure complete case ascertainment, data quality and data consistency in the two cities. For all sites combined, 75% of the cancers were verified histologically, 6% were diagnosed by direct observation, 8% were based on a clinical diagnosis, and 12.6% were ascertained by death certificate only. A standard set of analyses was carried out for each of the organs and organ systems considered. Depending on the cancer site, Dosimetry System 1986 (DS86) organ or kerma doses were used for computing risk estimates. Analyses were based on a general excess relative risk model (the background rate times one plus the excess relative risk). Analyses carried out for each site involved fitting the background model with no dose effect, a linear dose-response model with no effect modifiers, a linear-quadratic dose-response model with no effect modifiers, and a series of linear dose-response models that included each of the covariates (sex, age at exposure, time since exposure, attained age and city) individually as effect modifiers. Because the tumor registries ascertain cancers in the registry catchment areas only, an adjustment was made for the effects of migration. In agreement with prior LSS findings, a statistically significant excess risk for all solid cancers was demonstrated [excess relative risk at 1 Sv (ERR1Sv) = 0.63; excess absolute risk (EAR) per 10(4) person-year sievert (PY Sv) = 29.7]. For cancers of the stomach (ERR1SV = 0.32), colon (ERR1SV = 0.72), lung (ERR1SV = 0.95), breast (ERR1SV = 1.59), ovary (ERR1SV = 0.99), urinary bladder (ERR1SV = 1.02) and thyroid (ERR1SV = 1.15), significant radiation associations were observed. There was some indication of an increase in tumors of the neural tissue (excluding the brain) among persons exposed to the bombs before age 20. For the first time, radiation has been associated with liver (ERR1SV = 0.49) and nonmelanoma skin (ERR1SV = 1.0) cancer incidence in the LSS cohort. The present analysis also strengthened earlier findings, based on a smaller number of cases, of an effect of A-bomb radiation on salivary gland cancer.(ABSTRACT TRUNCATED AT 400 WORDS)

Dose and dose-rate dependence of the frequency of HPRT deficient T lymphocytes in the spleen of the 137Cs gamma-irradiated mouse.

The frequency of hypoxanthine phosphoribosyl transferase (HPRT) deficient splenic T lymphocytes was measured in the 137Cs gamma-irradiated mouse by the T cell cloning method. Doses from 0.3 to 6 Gy were applied at the dose-rates 0.5 Gy/min, 1 Gy/day and 1 Gy/week. Mutants were determined 8-10 and 30-40 weeks after the end of exposure. Radiation-induced mutant frequency (MFi) was calculated by subtracting the age corrected spontaneous mutant frequency (MFsp) from total mutant frequency (MF) found in irradiated animals. Data were fitted to linear and linear-quadratic dose-response models. MFi depended markedly on dose, dose-rate and time after exposure. When mutants were determined 8-10 weeks after acute irradiation (0.5 Gy/min) the dose-effect curve fitted the linear-quadratic equation MFi = 6.9 x 10(-6) Gy + 1.2 x 10(-6) Gy2, whereas in low dose-rate experiments (1 Gy/day, 1 Gy/week) the dose-effect curves were linear. The slope of the linear regression was about 3 x 10(-6). When low dose-rate-irradiated animals were killed 30-40 weeks after irradiation, MFi was about one-third of that observed after 8 weeks. The dose dose-rate effectiveness factor (DDREF) for radiation mutagenicity was calculated in animals that had been exposed 8-10 weeks previously. For doses < 2 Gy the reduction in effectiveness was about 1.5 when the irradiation dose-rate was < or = 1 Gy/day. For higher doses DDREF was 3-5.

The effect of fractionated doses of radiation on mouse spinal cord

Purpose : To determine: (a) the dose-response relationship and latent time to paralysis following fractionated doses of radiation in mice, (b) the values of parameters for isoeffect curves, and (c) whether these parameters depend on the size of dose per fraction and the severity of injury. Methods and Materials : The spinal cords (T 9-L 5) of 608 C 3Hf/Sed/Kam mice were irradiated with fractionated doses of x-radiation. Three levels of neurological damage were used to grade the spinal cord response. Animals which did not develop paralysis were observed for at least 18 months after irradiation. The fractionated schedules consisted of either 2, 3, 4, 6, 10, or 20 fractions in addition to single doses. For the fractionated regimes the daily fraction size ranged from 2 Gy to 24 Gy, and for single doses the range was 12 Gy to 52 Gy. Both the latent time to paralysis and the incidence of paralysis were considered as endpoints. For analysis of the sparing associated with fractionation, the dose points were divided into two groups: a “low damage” group consisting of doses of near or less than the ED 50 at 450 days and a “high damage” group consisting of doses much larger than the EDSO at 450 days in which there was 100% incidence of paralysis. Results : The latent time depended on the radiation dose; for each fixed fraction number the latent period became progressively shorter with higher total doses. Differences in histology in fractionation sensitivity are observed between the two groups. The low damage data in each fractionation treatment are the important data in the analysis of long-term incidence of paralysis. On the other hand, the high damage data were emphasized for the analysis of latency. Three statistical methods (mixture model, Cox model, and Fe-plot) were used to fit the linear-quadratic dose response model and the “Nominal Standard Dose” (NSD) model. The values of the parameters of these two models depended on the effect evaluated; the latent interval from the high damage region being not very fractionation-dependent, whereas, the incidence of paralysis from the low damage fractionation regimens was strongly dependent on dose per fraction. Specifically, the α/ β ratios for latency were large (e.g., 17 to 57 Gy) when fractionation schemes in the high damage region were emphasized. If data from the fractionation schemes in the lower damage region with fraction size less than 15 Gy were emphasized, the solα β ratios for incidence of paralysis were 3.3 (1.8, 6.0, 95% C.I.), 4.1 (2.8, 5.5), and 4.4 Gy derived by the mixture, Cox, and Fe-plot models, respectively. These “low damage” α β ratios were similar for all levels of injury from mild to complete paralysis, and are those which are more relevant to clinical radiotherapy. The coefficients for the “Nominal Standard Dose” formula in the present study were 0.33 ± 0.01 (s.e.) (by the Strandgvist-type plot), 0.38 (the Cox model), or 0.40 (the mixture model) for level 2 injury at 450 days. Conclusion : The values of parameters in the isoeffect models were different when the data analyzed were derived from regimens using fractionated low or high damage doses.

Time and dose dependency of bone-sarcomas in patients injected with radium-224.

The time course and dose dependency of the incidence of bone-sarcomas among 900 German patients treated with high doses of radium-224 is analysed in terms of a proportional hazards model with a log-normal dependency of time to tumor and a linear-quadratic dose relation. The deduced dose dependency agrees well with a previous analysis in terms of a non-parametric proportional hazards model, and confirms the temporal distribution which has been used in the Radioepidemiological Tables of NIH. However, the linear-quadratic dose-response model gives a risk estimate for low doses which is somewhat less than half that obtained under the assumption of linearity.

Radiation Carcinogenesis: Time-Dose Relationships

The present studies were undertaken to examine the time-dose relationships for the induction of lung adenocarcinomas and mammary adenocarcinomas in female BALB/c mice following gamma irradiation. Twelve-week-old female BALB/c/An NBd mice were irradiated with 137Cs gamma rays, and lifetime tumor incidences following high-dose-rate, low-dose-rate, or fractionated exposure regimens were compared. Analysis of the results indicated that the data could be fitted by linear-quadratic dose-response models for the induction of both tumors following acute doses and a linear model with a slope similar to that for the linear portion of the linear quadratic following low-dose-rate exposure regimens. When doses were fractionated the response was dependent upon the dose per fraction. If the dose per fraction was a dose which was predominantly on the linear portion of the acute dose response curve, then the response was linear and similar to that after low-dose-rate exposures. If the dose per fraction was in a region where the quadratic portion of the acute dose-response was significant, then the tumor incidence was higher than that following low-dose-rate exposures.

Radiation carcinogenesis in humans: is it necessary to revise exposure dose limits based on recent estimates of lifetime risks?

Radiation protection dose limits for populations and workers have been recommended on the basis of linear, no threshold dose response and constant absolute risk (AR) models. In 1980, the Committee on the Biological Effects of Ionizing Radiations (BEIR) showed that lifetime cancer risk is three times greater if the relative risk (RR) model is used instead of the AR model. Recently, several arguments have been advanced to promote the RR model to the detriment of the AR model. As a result, one may raise the question whether exposure dose limits should be reduced. This work shows that, together with the RR model, the linear-quadratic dose-response model has also been set forth as a competitor to the linear model. If the linear dose response and AR models are to be replaced by the linear-quadratic dose response and RR models, then lifetime risk predictions remain unchanged and a revision of exposure dose limits might be not necessary.

Effects of Cryopreservation on the Recovery of Radiation-Induced Chromosome Aberrations in Human Lymphocytes

Experiments were conducted to determine whether irradiated blood samples may be preserved by freezing without compromising the accurate assessment of radiation-induced chromosome aberrations in lymphocyte cultures initiated at later dates. Human whole blood at 37 oC was exposed in vitro to 0, 1.2, or 4 Gy cobalt-60 gamma radiation, and lymphocytes were cultured immediately after exposure or after one weeks storage at -70 oC. A slight depression in cellular proliferation and a significant increase in chromatid breakages were observed in cultures initiated from the previously frozen lymphocytes. In preparations from both fresh and frozen lymphocytes the dose response relationships for radiation-induced dicentrics and acentrics were adequately described by the linear-quadratic dose response model (Y = aD + ßD2) with no significant differences in the values of the alpha or beta coefficients between the two sets of cultures. This finding provides evidence that lymphocytes bearing radiation-induced chromosome aberrations are not at selective risk for cell death as a result of cryopreservation.