Sparing Effect Of Dose Fractionation Research Articles

ICRP PUBLICATION 118: ICRP Statement on Tissue Reactions and Early and Late Effects of Radiation in Normal Tissues and Organs – Threshold Doses for Tissue Reactions in a Radiation Protection Context

This report provides a review of early and late effects of radiation in normal tissues and organs with respect to radiation protection. It was instigated following a recommendation in Publication 103 (ICRP, 2007), and it provides updated estimates of ‘practical’ threshold doses for tissue injury defined at the level of 1% incidence. Estimates are given for morbidity and mortality endpoints in all organ systems following acute, fractionated, or chronic exposure. The organ systems comprise the haematopoietic, immune, reproductive, circulatory, respiratory, musculoskeletal, endocrine, and nervous systems; the digestive and urinary tracts; the skin; and the eye.Particular attention is paid to circulatory disease and cataracts because of recent evidence of higher incidences of injury than expected after lower doses; hence, threshold doses appear to be lower than previously considered. This is largely because of the increasing incidences with increasing times after exposure. In the context of protection, it is the threshold doses for very long follow-up times that are the most relevant for workers and the public; for example, the atomic bomb survivors with 40–50years of follow-up. Radiotherapy data generally apply for shorter follow-up times because of competing causes of death in cancer patients, and hence the risks of radiation-induced circulatory disease at those earlier times are lower.A variety of biological response modifiers have been used to help reduce late reactions in many tissues. These include antioxidants, radical scavengers, inhibitors of apoptosis, anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, growth factors, and cytokines. In many cases, these give dose modification factors of 1.1–1.2, and in a few cases 1.5–2, indicating the potential for increasing threshold doses in known exposure cases. In contrast, there are agents that enhance radiation responses, notably other cytotoxic agents such as antimetabolites, alkylating agents, anti-angiogenic drugs, and antibiotics, as well as genetic and comorbidity factors.Most tissues show a sparing effect of dose fractionation, so that total doses for a given endpoint are higher if the dose is fractionated rather than when given as a single dose. However, for reactions manifesting very late after low total doses, particularly for cataracts and circulatory disease, it appears that the rate of dose delivery does not modify the low incidence. This implies that the injury in these cases and at these low dose levels is caused by single-hit irreparable-type events. For these two tissues, a threshold dose of 0.5Gy is proposed herein for practical purposes, irrespective of the rate of dose delivery, and future studies may elucidate this judgement further.

Caffeine-Induced Apoptosis Reveals a Persistent Lesion after Treatment with Bromodeoxyuridine and Ultraviolet-B Light

Ultraviolet-B (UVB) light treatment of synchronized V79 Chinese hamster cells after pulse-labeling with bromodeoxyuridine (BrdUrd) reveals a marked age response for cell killing. Incubation after treatment in growth medium containing caffeine increases cell killing during the resistant portions of the cell cycle, resulting in a much less marked age response to UVB irradiation. Examination of the split-dose survival curves for BrdUrd and UVB light in the presence or absence of caffeine indicates that sensitization by caffeine is completely independent of the sparing effect of dose fractionation. Further, sensitization by caffeine is nearly complete after the first mitosis after the UVB exposure. With delayed addition of caffeine, however, nearly full sensitization can be elicited as late as two cell cycles after the treatment with BrdUrd and UVB light. Also, synchronized cells exposed to caffeine after treatment with BrdUrd and UVB in the S phase cease to incorporate radiolabeled thymidine and undergo apoptosis after the second mitosis. Thus exposure to caffeine reveals a persistent sensitivity lasting for at least two cell cycles, after the injury induced by treatment with BrdUrd and UVB.

Radioprotection of Mouse Hemopoiesis by Dipyridamole and Adenosine Monophosphate in Fractionated Treatment

The purpose of the studies reported here was to investigate the ability of the combined administration of dipyridamole and adenosine monophosphate, drugs known to elevate extracellular adenosine, to protect mice undergoing treatment with fractionated irradiation (five doses of 2 or 3 Gy each) given at 24-h intervals. Based on observations of hemopoietic recovery (endogenous hemopoietic spleen colony formation, marrow granulocyte-macrophage colony-forming cells, peripheral blood cells) after the completion of fractionated irradiation and on survival studies, it was demonstrated that the repeated administration of the drugs 60 min before each of the radiation fractions mitigates the hemopoietic injury and enhances the survival of mice irradiated with an additional "top-up" dose. It could be deduced that the single protective actions of the drugs retain their efficacy in repeated treatment and enhance the sparing effect of dose fractionation on hemopoiesis. Interestingly, the toxic side effects of the drugs tend to decrease when they are administered repeatedly, probably due to the development of tolerance to their cardiovascular action. This reduction in toxicity offers benefit with respect to the potential use of these hemopoiesis-protecting drugs in clinical radiotherapy.

The dose-fractionation sensitivity of the kidney; assessment of viable tubule cross-sections at 19 months after X irradiation.

The formation of viable tubule cross-sections was assessed in histological sections of murine kidneys at 19 months after fractionated bilateral X-ray doses with 12 h intervals between fractions. The data were analysed using the linear-quadratic model which provides values of alpha and beta characterizing the slope of the dose-response curve, and the ratio of alpha and beta indicative of the sparing effect of dose fractionation. The tubule data were characterized by alpha = 0.057 +/- 0.009 Gy-1, beta = 0.011 +/- 0.001 Gy-2, alpha/beta = 5.0 +/- 0.9 Gy. Also, the number of cells (per focus region of the nephron) calculated as being capable of producing a viable focus was 2.5 +/- 0.5, which was confirmed using a separate two-dose approach (2.1 +/- 0.3). Together with other data, of the order of 1000 regenerative cells per nephron (10(4) total cells) can be deduced. The values of the fractionation sensitivity parameters are similar to values measured previously for cells taken from irradiated kidneys up to a year after irradiation and forming colonies in primary culture, and also similar to values assessed using various functional measures of kidney injury.

Radiation studies on multicellular tumour spheroids derived from human neuroblastoma: Absence of sparing effect of dose fractionation

In vitro experiments were carried out to compare the effects of single-dose and split-dose irradiation on a cell line (NB1-G) derived from human neuroblastoma and grown as multicellular tumour spheroids (MTS). The radiation response was evaluated in terms of regrowth delay; estimates of in situ cell survival were made by back-extrapolation of regrowth curves. These studies showed no significant difference in the effectiveness of single as compared to split dose irradiation i.e. no sparing effect of fractionation. If MTS constitute a realistic model for micrometastases in vivo, these results provide a radiobiological rationale for hyperfractionated treatment regimes in the adjuvant radiotherapy of neuroblastoma.

Cataracts after total body irradiation and marrow transplantation: A sparing effect of dose fractionation

We examined 277 patients, who have been followed for 1 to 12 years after marrow transplantation, for cataract development. In preparation for transplantation, 96 patients with aplastic anemia were conditioned with chemotherapy only, usually cyclophosphamide 50 mg/kg × 4 intravenously, while 181 patients (two with aplastic anemia and 179 with a hematologic malignancy) were conditioned with a regimen of total body irradiation (TBI) and chemotherapy. TBI was delivered from two opposing 60Co sources at an exposure rate of 4 to 8 cGy/min, either as a single dose of 10 Gy (105 patients) or in fractions (76 patients), usually at increments of 2 to 2.25 Gy/day for 6 to 7 days for cumulative doses of 12 to 15.75 Gy. To date, 86 patients have developed cataracts. Kaplan-Meer product limit estimates of the incidence of cataracts for patients given chemotherapy only and no TBI, single-dose TBI, and fractionated TBI are 19, 80, and 18%, respectively. On the basis of proportional hazards regression analyses, patients given single-dose TBI had a relative risk of developing cataracts that was 4.7-fold higher than in patients given fractionated TBI or chemotherapy only ( p < 0.00005), suggesting a significant sparing effect with use of TBI dose fractionation. Additional significant risk factors included the chronic use of steroids post-transplant (highly associated with the presence of chronic graft-versus-host disease), and the diagnoses of acute lymphoblastic or chronic myelogenous leukemia.

The sparing effect of dose-fractionation in adult Drosophila.

The sparing effect of dose-fractionation was observed in adult male and female Drosophila melanogaster; 24-, 48-, 72-, and 96-h-old female flies, in general, show a higher recovery (increase in life-span) following dose-fractionation as compared to the males of the respective age. Recovery in 72-h-old females is maximal (31% increase in life-span) as against only 12% increase in the life span of the males.

Effect of single and fractionated doses of gamma radiation on pupariation of housefly.

Larvae of different ages from 40 hr to 72 hr were exposed to γ-rays ranging between 500R and 10000R ; all ages of the larvae showed dose-dependence pupariation delay up to 4000R. The shape of the puparia were not normal in the larvae irradiated with higher doses. Sparing effect of dose fractionation (SDF) was demonstrated for the pupariation delay. Sparing effect was quite marked at low dose-rate (15R/second) than at high dose-rate (80R/second) and maximum SDF was found with 2 hr interfraction interval as compared to 4.5 and 6.5 hr. The magnitude of SDF was comparatively less at 15°C than at 35°C indicating the occurrence of repair. Furthermore, the metabolic requirement of repair processes was evidenced by the abolition of SDF by inhibitors of energy metabolism, DNA binding agents and protein synthesis inhibitors.

Influence of X-ray dose fractionation on the frequency of somatic mutations induced in tradescantia stamen hairs

Abstract X-rays were used to investigate the influence of dose fractionation on the induction of pink and colorless somatic mutations in stamen hair cells of Tradescantia clone 02. Inflorescences were exposed to a single acute dose of 60 rad, two acute doses of 30 rad, or three acute doses of 20 rad. The dose rate in all cases was 30 rad/min. Intervals between dose fractions were varied from 35 sec to 48 h and the mutation frequency was compared with that resulting after the single dose of 60 rad. The data show a reduction in mutation frequency for fractionation intervals longer than 15 and 6 min for pink and colorless mutations, respectively, but not for shorter intervals. One interpretation of the data predicts that pink mutation frequencies are reduced by 11% for fraction intervals of from 30 min to 6 h, and that colorless mutation frequencies are reduced by 24% for intervals of from 15 min to 6 h. The corresponding sparing effect of dose fractionation is equal to 6 rad for pink mutations and 9 rad at the colorless mutation endpoint. A calculation has been made which indicates that the percentages of the total repairable (presumably two-hit) damage that is repaired during fraction intervals up to 6 h, are 16 and 35% for pink and colorless mutations respectively.

Split-dose and Liquid-holding Recovery after X-irradiation in Diploid YeastSaccharomyces Cerevisiae

Liquid-holding recovery (LHR) and the sparing effect of dose fractionation were investigated with 100 kVp-X-rays in diploid yeast from exponential and stationary phase. Exponential cells showed prompt and complete split-dose recovery. The ability to undergo LHR remained constant during 2-5 hours incubation after the first dose. Stationary-phase cells did not exhibit split-dose recovery (SDR) in a simple way: there was an increase in sensitivity after 3-5 hours followed by a gradual increases with time. It is suggested that stationary cells are starved of an essential co-factor which has to be synthesized de nova.

Action of a platinum complex [ cis-dichlorobis (cyclopentylamine)-platinum (II)] on chinese hamster ovary cells in vitro

cis-Dichlorobis(cyclopentylamine)platinum (II) (DBCP) treatment of Chinese hamster ovary (CHO) monolayer cell cultures was found to cause: (1) growth inhibition due to an impaired G 1→S transition and formation of a noncycling compartment; (2) delayed cell death (with a maximum at 72 h after treatment); (3) decrease of [ 14C] TdR incorporation into DNA. Part of the surviving cell population was subject to non-lethal damage. The D o values of the dose—survival curves were 9.2 and 14 mg/ml in two kinds of media differing in Na + and Cl − concentrations. There was no sparing effect of dose fractionation and no cell cycle phase specificity. In the dose range corresponding to the shoulder region of the dose—survival curve, the lethal effect of DBCP treatment was directly related to the decreased rate of DNA synthesis in DBCP-treated cells.

Acute Lethality after Fast-Neutron and X-Irradiation of Tribolium confusum

The acute lethal effects of fast neutrons and of X-rays on adults and larvae of T. confusum are compared. The time course of mortality of adults of the Oklahoma strain was the same after midlethal doses of neutrons and X-rays, although the neutrons were about twice as effective as X-rays in producing lethality, based on ${\rm LD}_{50(35)}$. The neutron RBE for adults of the Ebony mutant strain was also about 2, but that for Oklahoma larvae was about 3.85. Larvae surviving midlethal doses of neutrons showed a tendency toward wing abnormalities and delayed pupation. Dose-fractionation recovery with neutron doses in the midlethal range was not detectable in the adults or in the larvae. A considerable sparing effect of dose fractionation was found in X-irradiated adults. Also presented are techniques for using a beam port of a Triga research reactor for fast-neutron irradiation and a method of neutron and gamma dosimetry.

Noncytokinetic Injury: Sparing Effect of Dose Fractionation for Delay of Pupariation of the Fleshfly, Sarcophaga bullata Parker

Pupariation delay after irradiation of larvae of dipterous insects represents a precisely measurable form of noncytokinetic injury. A sparing effect of dose fractionation was demonstrated for this phenomenon. Sarcophaga bullata Parker were irradiated during the precritical period of the last larval instar. Pupariation delay is a function of dose from 1400 R to 4200 R; a sparing effect of dose fractionation was demonstrable over this entire range of doses.

The effect of some nucleic acid-binding metabolic inhibitors on split-dose sparing in u.v.-and electron-irradiated diploid yeast.

The following compounds (known to bind to DNA) were tested for their effect on split-dose sparing in yeast cells: acriflavine (10/sup -4/ m), hydroxylamine (10/sup -2/ m), caffeine (0.5%), formaldehyde (10/sup -3/ m), and actinomycin D (5 g/ml). Stationary diploid yeast cells were exposed to ultraviolet (254 nm) or 12-MeV electrons, using doses to result in a colony- forming ability of about 50% after one fraction (2 x 50 krad or 2 x 1180 erg mm/ sup -2/, respectively). The sparing effect of dose fractionation was inhibited with all compounds, except for acriflavine (ineffective with uv irradiation) and formaldehyde which prevented sparing only under hypoxic conditions. (UK)

The Importance of Cellular Energy Metabolism for the Sparing Effect of Dose Fractionation with Electrons and Ultra-violet Light

SummaryThe sparing effect of dose fractionation with electron and u.v. exposure was investigated in diploid yeast Saccharomyces cerevisiae. Sparing was observed at the same rate and to the same extent in air or under hypoxia if the cells were held in a glucose-containing nutrient medium. With non-fermentable substrates, e.g. lactate or acetate, the process was slower in the aerated sample, and absent in hypoxia. The action of some metabolic inhibitors known to interfere with cellular energy production was also studied. The sparing effect was diminished if ATP production was inhibited at an early stage of the metabolic pathway. The results are interpreted by assuming that energy-rich metabolites are essential for the sparing effect. Implications for radiotherapy are discussed.