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On the biophysical interpretation of the mathematical product of dose and relative biological effectiveness.

The mathematical product of dose and relative biological effectiveness (DR) is commonly used empirically as the 'effective' dose of radiations. It is often interpreted as the equivalent dose of a reference radiation, such that the individual DRs of the radiation components are summed like physical doses in a mixture of radiations with different RBE values. It is shown that such a physical interpretation of DR would be both mathematically and logically inconsistent unless the action of each radiation has a constant RBE value for all end-effects. This is contrary to general experimental findings. Based on the isoeffect biological connotation in the definition of RBE, a biophysical interpretation is being introduced in this paper in which DR is always interpreted with respect to a particular end-effect on which the RBE value is evaluated, somewhat similar to having an extra biological dimension. Hence, only DRs evaluated for the same end-effect can be meaningfully computed together in a mixture. From the empirical results of radiobiological experiments using mixtures of radiations of different qualities, DRs of radiation components are shown to be additive in a mixture just like physical doses. A convenient linear computation framework is, therefore, available for the use of DRs in the empirical calculation of effect of mixtures of radiations of different qualities. The bearing of this biophysical interpretation of DR on radiation protection and treatment planning is discussed.

Biophysical Phenomena

252Cf relative biological effectiveness and inheritable effect of fission neutrons in mouse liver tumorigenesis.

To determine the relative biological effectiveness of 252Cf fission neutrons versus 60Co gamma-rays for inducing liver tumorigenesis, C57BL/6NCrj x C3H/NCrj F1, hereafter called B6C3F1, mice were irradiated once either with 252Cf or 60Co and the tumorigenicity of the two types of radiation was studied. Individual groups of B6C3F1 mice (about 30 mice/group) were irradiated once with 252Cf at doses of 0, 3, 6, 12.5, 50, and 200 cGy for males and 0, 12.5, 50, and 200 cGy for females or with 60Co at doses of 0, 12.5, 50, and 200 cGy for both sexes. The groups were observed for 13 months after irradiation. The incidence of hepatic tumors in nonirradiated controls was 3.8% in males and 3.2% in females. 252Cf irradiation increased the incidence dose dependently in males and females, but less efficiently in females. The mean number and size of hepatic tumors were well correlated with tumor incidence. In contrast, 60Co was less efficient at inducing tumors. The relative biological effectiveness of 252Cf compared to 60Co was quite high in the low-dose range. Overall, the average relative biological effectiveness of 252Cf versus 60Co was 15.2 in males and 2.5 in females. In another experiment, 7-week-old male C3H mice, which are known to be carriers of hepatic tumorinogens, and that were the fathers of the B6C3F1 mice, were irradiated with 0, 50, and 200 cGy of 252Cf, and 2 weeks later they were mated with nonirradiated female C57BL mice. The control mice had nonirradiated fathers. The incidence of hepatic tumors in the offspring of irradiated fathers was 43% in males and 1.7% in females, whereas in the offspring of control mice with nonirradiated fathers the incidence was 3.2% in males and 3.3% in females. The multiplicity of the hepatic tumors was similar to the tumor incidence. Thus our results indicated a strong hepatocarcinogenic potential for 252Cf neutrons compared to 60Co gamma-rays, and that the cancer-prone genetic trait activated by 252Cf irradiation was inherited by first-generation offspring, especially in males.

Animals

[Quantitative description of the process of cellular radiation inactivation. IX. Remarks on the relative biological effectiveness of ionizing radiations in the reproductive death of diploid and polyploid cells].

The relative biological effectiveness (RBE) has been considered for three kinds of cell radiation damages: subdamages (sublethals), one-track, and two-track lethal damages. In contrast to the "dual theory", which postulates the square relation between the lethal damage yield and the specific energy, it is assumed that the one-track lethal yield is linearly related to the specific energy per cell nucleus. As a result, the identical dependence has been obtained of both one-track lethals and subdamages on specific energy and absorbed dose. It is established that RBE for all three kinds of damages does not depend on the radiation dose. It is shown that RBE for subdamages and one-track lethals depends on LET of radiation only, and involves molecular parameters of sensitive cell structures. Within the limits of this assumption, the relations are general for all the types of eukaryotic cells. These can be used for a further development of the RBE theory, with spectra of LET, the track structure of charged particles, the contribution of delta-electrons etc being taken into consideration.

Cell Division

The relative biological effectiveness of 10B-neutron capture therapy for early skin reaction in the hamster.

The relative biological effectiveness (RBE) of 10B-neutron capture therapy (BNCT) on skin was analyzed using hamsters. The Kyoto University Research Reactor, which has a very low contamination of gamma rays and fast neutrons, was used as a thermal neutron source. Boron-10-para-boronophenylalanine hydrochloride ([10B]BPA.HCl) was administered to the hamsters. The evolution and time course of early skin reactions were assessed. These reactions were compared with those produced by electron beams. The maximum safe skin doses (no more than moist desquamation) of BNCT and electron beams were established to be 11 and 21 Gy, respectively. The RBE at this single dose with BNCT was found to be 1.94, assuming that the RBE of the gamma rays was 1.0 and each component of BNCT (mixed radiations) was simply additive.

Animals

Relative biological effectiveness of high-energy photons (up to 50 MV) and electrons (50 MeV).

In vitro studies of the relative biological effectiveness (RBE) of 50-MV X rays have shown an RBE of 1.1 relative to 4-MV X rays. This will be important in clinical radiotherapy. The aim of this study was to verify these results and to investigate whether photonuclear processes might cause the difference in RBE. To do so, 50- and 20-MV X rays and 50-MeV electrons were investigated with respect to RBE. Chinese hamster V79 cells were irradiated in a specially designed system which allows for a high reproducibility of geometry and dosimetry. Fractionation experiments were also carried out to establish the RBE at the clinically relevant dose level, 2 Gy. Fricke dosimetry was used, and the results were confirmed with ionization chamber measurements. The RBE for 50-MV X rays was estimated to be 1.14 at a surviving fraction of 0.1 and 1.12 at a surviving fraction of 0.01. The RBEs for the other qualities were equal to one. The RBE calculated for the 2 Gy/fraction experiments was 1.17.

Animals

Relative biological effectiveness of 50-MV X rays on jejunal crypt survival in vivo.

Earlier in vitro studies of relative biological effectiveness (RBE) of 50-MV X rays show an RBE of approximately 1.1 compared to 4 MV. No difference in RBE has been found for 20-MV X rays or 50-MeV electrons. The higher RBE for 50 MV can be explained to some extent by the small high linear energy transfer contribution from photonuclear reactions at high X-ray energies. To investigate the validity of the results in vitro, a study of the RBE of 50-MV X rays has been performed in vivo using the jejunal crypt microcolony assay in mice. The reference radiation used in this case was 20-MV X rays. The results confirm the earlier in vitro studies. The RBE for 50-MV X rays was estimated to be 1.06, calculated as the ratio between the slopes of the response curves.

Animals

The relative biological effectiveness of photon radiation from encapsulated iodine-125, assessed in cells of human origin: I. Normal diploid fibroblasts.

The relative biological effectiveness (RBE) of photon radiation from encapsulated Iodine-125 "seed" sources has not previously been investigated in human cells. The RBE of 125I photons relative to 137Cs gamma rays was examined in normal diploid human fibroblasts derived from lung and skin. The cells were irradiated in plateau phase using a specially designed incubator-irradiator which permitted simultaneous 125I and 137Cs irradiation. The cells were irradiated at various dose rates ranging from 7 to 70 cGy/hr. Dosimetry was performed using Monte Carlo computer calculations to simulate the 125I irradiations and the exposure-standardization measurements made by the U.S. National Bureau of Standards which are the basis for the specified strengths of 125I seeds. Simulation of the exposure standardization measurements revealed systematic errors due to the unrecognized presence of low-energy fluorescence X rays. The specified activity of the type of seeds used for this study (high-activity, no radiographic marker) was found to be too high by more than 10%. The RBE of 125I assessed with both lung fibroblast lines was found to be 1.2 and was 1.3 for the skin fibroblasts. The RBE did not change over the range of dose rates tested. In fact, for both 125I and 137Cs, the dose response curves did not change with dose rate over the range tested, implying full repair of sublethal damage at dose rates below 70 cGy/hr in these non-dividing cells.

Brachytherapy

The relative biological effectiveness of fractionated doses of fast neutrons (42 MeVd----Be) for normal tissues in the pig. IV. Effects on renal function.

The effects of fractionated doses of fast neutrons (42 MeVd----Be) on the radiation response of the pig kidney have been assessed and compared with those observed after X irradiation. Following X irradiation there was a marked increase in the total dose at which renal function was preserved with decreasing fraction size. The rate of this increase was dependent on the overall treatment time; for fractionated irradiation given over 18 or 39 days the exponents related to fraction number, N, were 0.36 +/- 0.03 and 0.48 +/- 0.003, respectively. In contrast, there was no significant change in the iso-effect dose for renal injury following fractionated irradiation with fast neutrons where there was also little effect of varying the overall treatment time. Analysing these data by means of the linear-quadratic (LQ) model, using both an Fe-plot and the Tucker test, gave alpha/beta ratios of 2.42 +/- 0.06 Gy and 2.99 +/- 0.16 Gy, respectively, for X-ray doses given in 18 days. For fractionated doses of X rays given in 39 days the alpha/beta ratios were 0.40 +/- 0.01 Gy and 0.47 +/- 0.02 Gy, respectively. The alpha/beta ratios for renal tissue following fast neutron irradiation obtained by the two methods were also similar, i.e. 15.00 +/- 0.60 Gy and 15.72 +/- 3.76 Gy, respectively. The pronounced fractionation effect seen with X irradiation, particularly for doses administered over 39 days as opposed to 18 days, coupled with the absence of any such effect with fast neutrons, resulted in a marked increase in relative biological effectiveness (RBE) with decreasing X-ray dose/fraction. The slopes of the resulting regression lines were -0.73 +/- 0.05 and -0.33 +/- 0.02, respectively. The lack of dose sparing associated with fractionation, or variation of the overall treatment time for fast neutron irradiation, suggests that doses administered to tumours adjacent to the kidney can be given as a few relatively large dose/fractions in a short overall treatment time without an increased risk of complications related to renal tissue. This may be of therapeutic advantage in the treatment of rapidly proliferating tumours where dose may be wasted using more conventional protracted fractionated irradiation schedules.

Animals

The relative biological effectiveness of 60Co gamma-rays, 55 kVp X-rays, 250 kVp X-rays, and 11 MeV electrons at low doses.

The relative biological effectiveness (RBE) of selected low-LET radiation modalities (55 kVp X-rays, 250 kVp X-rays, 60Co gamma-rays, and 11 MeV electrons) was investigated for survival of two cell lines (V79 and CHO). Detailed measurements were made in the low (0 to 3 Gy) dose range using an image cytometry device to accurately determine the number of cells assayed at each dose point. Data were also collected in the high dose range (0 to 10 Gy) using conventional counting and plating techniques. RBE values (+/- 1 SE) varied from 1.0 +/- 0.07 (V79 cells) and 1.2 +/- 0.05 (CHO cells) at high doses to 1.3 +/- 0.07 (V79) and 1.4 +/- 0.1 (CHO) at low doses for 55 kVp X-rays, from 1.1 +/- 0.05 (V79) and 1.1 +/- 0.04 (CHO) at high doses to 1.1 +/- 0.06 (V79) and 1.2 +/- 0.2 (CHO) at low doses for 250 kVp X-rays, and from 1.1 +/- 0.08 (V79) and 1.0 +/- 0.04 (CHO) at high doses to 1.0 +/- 0.06 (V79) and 0.9 +/- 0.1 (CHO) at low doses for 11 MeV electrons. Only the low and high dose RBEs for 55 kVp X-rays relative to 60Co gamma-rays were significantly different.

Animals

Relative biological effectiveness of low- and high-LET radiotherapy beams for jejunal crypt cell survival at low doses per fraction.

In order to determine the relative biological effectiveness (RBE) of various low- and high-LET radiotherapy beams of low coses, LAF1 mice were exposed to one dose and 10 equally fractionated doses of 60Co gamma rays, 137Cs gamma rays, 4-MeV x rays, 300-kVp x rays, helium ions in the plateau and Bragg-peak region, and 15-MeV neutrons; survival of jejunal crypt cells with the microcolony assay of Withers and Elkind was determined using 60Co as the standard. RBE values for the survival of 10 cells/circumference for 10 fractionated exposures (2.4 Gy [240 rad] per fraction of 60Co) were: 1.07 for 137Cs, 1.06 for 4-MeV x rays, 1.16 for 300-kVp x rays, 1.10 for helium ions in the plateau, 1.29 for helium ions in the peak, and 3.02 for 15-MeV neutrons. As LET increased, RBE increased with decrease of dose/fraction.

Animals

The relative biological effectiveness of fractionated doses of fast neutrons (42 MeVd----Be) for normal tissues in the pig. II. Late effects on cutaneous and subcutaneous tissues.

The late effects of irradiation with single and fractionated doses of X rays (250 kV) and fast neutrons (42 MeVd----Bc), on the cutaneous and subcutaneous tissues of the pig, have been evaluated from measurements of changes in relative field length. These were determined at intervals of 26-104 weeks after irradiation. For fractionated irradiation with X rays the average fractions exponent, N, obtained from a log-log plot of iso-effect dose (ED50) against fraction number was 0.41. This was independent of the period of assessment, with no significant indication of a time factor. However, the exponent N did vary with the level of effect and was in the range 0.33-0.51. It was greatest for a greater than or equal to 10% reduction in relative field length. Assuming the validity of the linear quadratic model of cell survival, the alpha/beta ratio was 1.95 Gy. However, this model fitted the data less well for the least severe levels of damage, and for these the alpha/beta ratios were not significantly different from zero. Irradiation with fast neutrons showed a small effect of fractionation for doses given in greater than or equal to 6 fractions compared with a single dose. There was no significant increase in iso-effect dose when the dose was given in 30 fractions compared with 6 fractions. The relative biological effectiveness for late cutaneous and subcutaneous damage for the energy of fast neutrons used did not vary with the period of assessment, i.e. 26-52 weeks compared with 65-104 weeks, and was not significantly different from that previously obtained for ischaemic dermal necrosis, seen after higher doses, at 12-20 weeks after irradiation.

Animals

The relative biological effectiveness of mixed fission-neutron-gamma radiation on the hematopoietic syndrome in the canine: effect of therapy on survival.

Acute lethality syndromes produced by the accidental exposure of humans to mixed neutron and gamma radiation from external sources can be related to acute lethality from photon irradiation using the relative biological effectiveness (RBE) for common end points. We used the canine as a model to study injury following exposure to mixed neutron and gamma radiation from the AFRRI TRIGA reactor. Exposures from the reactor were steady-state mode (40 cGy/min, bilateral) with an average neutron energy of 0.85 MeV; tissue-air ratio = 0.59 at midline abdominal. Healthy male and female canines were irradiated free-in-air behind a 6-in. lead wall; the neutron-gamma ratio was 5.4:1 at the entrance skin surface; exposures are reported as midline tissue doses. Bilateral exposure resulted in an LD50/30 of 153 cGy without therapeutic clinical support. Addition of clinical support consisting of fluids, antibiotics, and fresh irradiated platelets/whole blood increased the bilateral LD50/30 to 185 cGy, a dose modifying factor (DMF) of 1.21. This corresponds to respective LD50/30 values for bilateral 60Co gamma exposures of 260 and 338 cGy for nonsupported and clinically supported animals, and a DMF of 1.30. The RBE based on the values determined at midline tissue is approximately 1.69. Clinical support after bilateral irradiation produced a similar DMF to those of mixed fission neutrons and gamma rays and 60Co gamma rays alone. The RBE of 1.69 for midline tissue bilateral exposures is higher than 1, an RBE often cited for large animals. Therapeutic support administered to lethally irradiated canines significantly improved survival and increased the LD50/30 independent of radiation quality.

Animals

[Cytogenetic effects induced in vitro in human peripheral blood lymphocytes by neutrons. II. Relative biological effectiveness of neutrons having different energies].

Human lymphocytes were irradiated in vitro during Go stage by graded doses of thermal neutrons and neutrons having an average energy of 0.04; 0.09; 0.35; 0.85 and 14,7 MeV as well as by 60Co gamma rays, and RBE of neutrons relative to gamma-rays was calculated for the frequency of total and different types of aberrations. It was found that the RBE has the most value at the low doses and decreases when the exposition dose increases. 0.35 MeV neutrons have the maximum RBE in comparison with neutrons having other energies. When comparing the RBE values calculated for different types of chromosome aberrations, it was found out that dicentrics and dicentrics plus centric rings had more RBE than acentric aberrations (pair fragments and minutes).

Chromosomes, Human

Relative biological effectiveness for neutron carcinogenesis in monkeys and rats.

The risks of total-body irradiation with large doses of X rays (average dose 6.7 Gy) and fission neutrons (average dose 3.4 Gy) were investigated by keeping a group of long-term surviving monkeys from an experiment on acute effects under continuous observation. On the basis of the number of animals developing tumors in each group as a function of the total observation period and the average absorbed dose, relative biological effectiveness (RBE) values between 4 and 5 have been derived at these high dose levels. In experiments on mammary carcinogenesis in rats the highest RBE values are observed for neutrons with energies of 0.43 to 1 MeV as produced by the p + T reaction or by the fission process. Based upon linear dose-response curves for neutrons and X rays, a maximum RBE value of 15 was observed for induction of adenocarcinomas in WAG/Rij rats. Appreciably higher RBE values would be obtained if the results of the gamma-ray exposure, indicating a nearly quadratic dose-response relationship, were used as a baseline. For radiation protection applications it should be realized, however, that such an increase will be caused by the lower efficiency of low-linear-energy-transfer radiation rather than by an increase in efficiency of the neutron irradiation at low doses.

Adenocarcinoma

Clinical study of relative biological effectiveness for cervical carcinoma treated by 252Cf neutrons and assessed by histological tumour eradication.

Clinical data of the University of Kentucky trial using californium (252Cf), or caesium (137Cs), are reviewed for dose-response based on the endpoint of tumour eradication estimated from hysterectomy specimens obtained 4-6 weeks after preoperative irradiation. These data are used to assess the relative biological effectiveness (RBE) for 252Cf neutrons compared with 137Cs gamma radiation. Tumours treated were of common stage but were of bulky or barrel shape suitable for "radiosurgical" therapy. Dose-response curves were constructed, and additional data from the literature used to analyse the curve shape. The photon dose-response curve is complex on a logarithmic plot, whereas the 252Cf neutron curve is exponential. This indicates that the RBE can be different depending on the number of implants, schedule and size of dose delivered per session. The RBE values were approximately 8.0 at low doses or for multiple implants but they may rise to approximately 16 at larger doses or for single 252Cf implants.

Brachytherapy