Fifteen symposia on microdosimetry: implications for modern particle-beam cancer radiotherapy.

The objective of microdosimetry was, and still is, to identify physical descriptions of the initial physical processes of ionising radiation interacting with biological matter which correlate with observed radiobiological effects with a view to improve the understanding of radiobiological mechanisms and effects. The introduction of therapy with particles starting with fast neutrons followed by negative pions, protons and light ions necessitated the application of biological weighting factors for absorbed dose in order to account for differences of the relative biological effectiveness (RBE). Dedicated radiobiological experiments in therapy beams with mammalian cells and with laboratory animals provided sets of RBE values which are used to evaluate empirical 'clinical RBE values'. The combination of such experiments with microdosimetric measurements in identical conditions offered the possibility to establish semi-empirical relationships between microdosimetric parameters and results of RBE studies.

Interaction of alpha particles at the cellular level--implications for the radiation weighting factor.

Since low dose effects of alpha particles are produced by cellular hits in a relatively small fraction of exposed cells, the present study focuses on alpha particle interactions in bronchial epithelial cells following exposure to inhaled radon progeny. A computer code was developed for the calculation of microdosimetric spectra, dose and hit probabilities for alpha particles emitted from uniform and non-uniform source distributions in cylindrical and Y-shaped bronchial airway geometries. Activity accumulations at the dividing spur of bronchial airway bifurcations produce hot spots of cellular hits, indicating that a small fraction of cells located at such sites may receive substantially higher doses. While presently available data on in vitro transformation frequencies suggest that the relative biological effectiveness for alpha particles ranges from about 3 to 10, the effect of inhomogeneous activity distributions of radon progeny may slightly increase the radiation weighting factor relative to a uniform distribution. Thus a radiation weighting factor of about 10 may be more realistic than the current value of 20, at least for lung cancer risk following inhalation of short-lived radon progeny.

Monte Carlo code for microdosimetry of inhaled alpha emitters.

A Monte Carlo code has been developed to calculate the local energy deposited by alpha emitters deposited on the inner surface in the lung airway. Developed to deal further with airway bifurcations, this code has been as a first step validated in a cylindrical airway configuration by comparison with well-established analytical codes in the case of contamination of bronchiolar airways with actinides. The code has then been applied to the study of uniform and non-uniform contamination of cylindrical bronchial airways by radon progeny in indoor and mine exposure conditions. In addition to the microdosimetric spectra, the average microdosimetric parameters (zp, n, z) have been evaluated. The work currently in progress consists in adapting this developed Monte Carlo code to the configuration of an airway bifurcation with realistic particles deposition.

Determination of the physical and chemical properties, biokinetics, and dose coefficients of uranium compounds handled during nuclear fuel fabrication in France.

The introduction of new ICRP recommendations, especially the new Human Respiratory Tract Model (HRTM) in ICRP Publication 66 led us to focus on some specific parameters related to industrial uranium aerosols collected between 1990 and 1999 at French nuclear fuel fabrication facilities operated by COGEMA, FBFC, and the CEA. Among these parameters, the activity median aerodynamic diameter (AMAD), specific surface area (SSA), and parameters describing absorption to blood f(r), s(r) and s(s) defined in ICRP Publication 66 were identified as the most relevant influencing dose assessment. This study reviewed the data for 25 pure and impure uranium compounds. The average value of AMAD obtained was 5.7 microm (range 1.1-8.5 microm), which strongly supports the choice of 5 microm as the default value of AMAD for occupational exposures. The SSA varied between 0.4 and 18.3 m2 g(-1). For most materials, values of the absorption parameters f(r), s(r), and s(s) derived from the in vitro experiments were generally consistent with those derived from the in vivo experiments. Using average values for each pure compound allowed us to classify UO2 and U3O8 as Type S, mixed oxides, UF4, UO3 and ADU as Type M, and UO4 as Type F based on the ICRP Publication 71 criteria. Dose coefficients were also calculated for each pure compound, and average values for each type of pure compound were compared with those derived using default values. Finally, the lung retention kinetics and urinary excretion rates for inhaled U03 were compared using material-specific and default absorption parameters, in order to give a practical example of the application of this study.

Dosimetry and microdosimetry of targeted radiotherapy.

Dosimetry in targeted radiotherapy (TR) uses different calculation methods, whose degree of refinement is closely conditioned by the particular objective sought. It is more generally performed to establish a correlation between the quantity of radiation delivered to a target and the biological damage observed or that can be reliably predicted. It can thus be used to optimise treatments and allow comparison of different therapeutic approaches, as well as to study the basic methods of irradiation of biological matter. Two broad types of investigations can be found in the literature: microdosimetric ones (stochastic approaches used to study energy deposits) and macrodosimetric ones (non-stochastic or deterministic approaches). The mathematical formalism is consistent between these two types, and the calculation methods currently used are often similar. This review presents different approaches to the dosimetry of radionuclides used in TR. The introduction defines the general problem, the role of dosimetry in TR and the specific problems raised by targeting (non-uniformity of source distributions). The first part considers the types of calculation methods found in TR in relation to the basic quantities used to represent stochastic energy deposit on a cellular scale. In particular, it compares the formalism and the methods used in microdosimetric or conventional macrodosimetric approches. Although microdosimetry, or even track structure calculations, can provide the basic elements for modelling the absorbed dose process, a simplified dosimetric approach may be adequate to describe the phenomena observed. The scheme proposed by the MIRD committee relates to such an approach and is presented together with other methods allowing the calculation of the mean dose delivered (analytic methods, dose point kernels, Monte-Carlo, etc.). The second part shows the application range for the various methods, providing selected examples of dosimetric approaches in TR on different scales, from the organ (or tissues) to the cell or even DNA, and a brief presentation of bone marrow dosimetry.

Risk assessment for cancer induction after low- and high-LET therapeutic irradiation.

The risk of induction of a second primary cancer after a therapeutic irradiation with conventional photon beams is well recognized and documented. However, in general, it is totally overwhelmed by the benefit of the treatment. The same is true to a large extent for the combinations of radiation and drug therapy. After fast neutron therapy, the risk of induction of a second cancer is greater than after photon therapy. Neutron RBE increases with decreasing dose and there is a wide evidence that neutron RBE is greater for cancer induction (and for other late effects relevant in radiation protection) than for cell killing. Animal data on RBE for tumor induction are reviewed, as well as other biological effects such as life shortening, malignant cell transformation in vitro, chromosome aberrations, genetic effects. These effects can be related, directly or indirectly, to cancer induction to the extent that they express a "genomic" lesion. Almost no reliable human epidemiological data are available so far. For fission neutrons a RBE for cancer induction of about 20 relative to photons seems to be a reasonable assumption. For fast neutrons, due to the difference in energy spectrum, a RBE of 10 can be assumed. After proton beam therapy (low-LET radiation), the risk of secondary cancer induction, relative to photons, can be divided by a factor of 3, due to the reduction of integral dose (as an average). The RBE of heavy-ions for cancer induction can be assumed to be similar to fission neutrons, i.e. about 20 relative to photons. However, after heavy-ion beam therapy, the risk should be divided by 3, as after proton therapy due to the excellent physical selectivity of the irradiation. Therefore a risk 5 to 10 times higher than photons could be assumed. This range is probably a pessimistic estimate for carbon ions since most of the normal tissues, at the level of the initial plateau, are irradiated with low-LET radiation.

Specification of radiation quality in fast neutron therapy: microdosimetric and radiobiological approach.

Specification of radiation quality is an important issue in fast neutron therapy since the biological effectiveness of the beams varies to a large extent with neutron energy. It must meet specific criteria, mainly derived from the accuracy requirement for absorbed dose delivery. A first approach to this problem consists in identifying physical parameters that can be related to Relative Biological Effectiveness (RBE) and which describe the beam production technique (e.g. neutron-producing reaction, p + Be or d + Be, energy of the incident particle). A second is based on microdosimetry, which provides a description of the secondary radiation components to which the biological consequences of irradiations are more directly correlated. A third approach consists in experimental RBE determinations in reference conditions: intestinal crypt regeneration in mice after irradiation to the whole body with single doses is proposed as a standard biological system for radiobiological calibrations of clinical fast neutron beams. Dosimetric, microdosimetric and radiobiological intercomparisons are encouraged since they provide a homogeneous set of data which facilitate the exchange of clinical information. They also constitute a basis for the clinical RBE approach and an overall check of the irradiation procedure. Therefore they should be recommended in every non-conventional radiation therapy facility.

Análise de radioelementos, a níveis de traços, utilizando espectrometria de massa de íons secundários / Analysis of radioelements by levels of traits using mass spectrometry of secundary ions

A espectrometria de massa de íons secundários (SIMS) permite a detecção rápida de elementos estáveis ou radioativos, bem como o cálculo de seu percentual isotópico. Ademais, essa técnica possibilita a localização de radioisótipos, à níveis de traços, em amostras biológicas. Neste trabalho procurou-se estudar a utilização dessa metodologia na detecção de urânio natural à baixa concentração. Estudos sobre a preparação de amostras e limites de detecção foram também realizados.

The clinical RBE and microdosimetric characterization of radiation quality in fast neutron therapy.

High-LET radiation therapy using fast neutrons is being applied regularly at several centres worldwide and in the future, other types of radiation qualities, such as protons and heavier ions and boron neutron capture therapy (BNCT) are likely to be used. The neutron beams used are of considerably varying energy and thus considerable variations in the relative biological effectiveness (RBE) have been found. At present, no generally accepted method exists for the quantitative specification of these differences in radiation quality for clinical purposes. This is in clear discrepancy with the accuracy requirements in clinical dosimetry. An approach is presented which is based on a single parameter radiation quality characterization determined in combined microdosimetric and radiobiological experiments. It is shown that the method can meet the accuracy requirements of clinical dosimetry and that it is applicable within a concept of formalized procedure of clinical practice and experience ('clinical RBE').

Microdosimetric specification of radiation quality in neutron radiation therapy.

The neutron beams used by various radiotherapy centres are of widely differing energies, and differences of up to 50 per cent in the relative biological effectiveness (RBE) between different beams have been found in radiobiological experiments. Moreover, at some facilities RBE variations have been observed with increasing depth in a phantom. In spite of this evidence, there is no quantitative and uniquely accepted specification of radiation quality used in practice. The urgency of an adequate solution of this problem is illustrated by the fact that in radiation therapy the usual accuracy requirement for the quantity of radiation, i.e. the absorbed dose to be delivered to the tumour, is 3.5 per cent (1 SD). In this paper a pragmatic solution for the specification of radiation quality for fast neutron therapy is proposed. It is based on empirical RBE versus lineal energy response or weighting functions. These were established by using existing radiobiological data and microdosimetric spectra measured under identical irradiation conditions at several European neutron irradiation units.

Results of 10 y of radiation protection dosimetry at the neutrontherapy facility in Louvain-la-Neuve.

After 10 y of routine operation, radiation hazards to the neutron therapy staff at Louvain-la-Neuve were evaluated. These hazards to the staff in neutron therapy are a matter of concern, not only because of the dose levels due to induced activation after treatment but also because of the difficulty of evaluating adequately the dose equivalent rates (including the quality factor, QF) during the irradiation. Build-up of radioactivity near the collimator and in the therapy room is reported. In the beam axis, dose rates due to activation can amount up to 5 mGy h-1. However, these rates are efficiently reduced to 0.3 mGy h-1 by automatically withdrawing the target after irradiation. Other problems of radioactive contamination (for instance, the choice of the Fe composition of the collimator) are discussed. Dose equivalent rates were determined during treatment at different positions inside and outside the treatment room. At these locations, neutrons of widely varying energies are present, accompanied by a significant proportion of gamma rays. The measurements of neutron-dose equivalent rates were performed with three commercial neutron detectors: a BF3 and a He3 remcounter (Nuclear Enterprises and Nardeux) and the Dineutron multisphere remcounter (Nardeux). The Dineutron also allowed the evaluation of QF. The results of these detectors were compared with the results of the integration of microdosimetry spectra obtained in free air with a TE proportional counter (Far West Technology). For the p(65) + Be neutrons, the dose equivalent rate was equal to 0.4 Sv h-1 in the treatment room (at 2.5 m from the collimator) and was reduced to 2-3 microSv h-1 at the room entrance. The gamma component increased from 55% to 95% at the same positions, respectively. Ratios of the responses of all detectors and QF values are compared and discussed at the different positions. The whole-body dose equivalents to the neutron therapy staff over the 10 y considered are presented; although they are higher than for conventional radiotherapy, they remain far below the ICRP recommended dose limits.

[Comparative kinetics of the early repair of intestines and lung in mice after fast neutron and gamma-ray irradiation]. / Cinétiques comparées de la réparation précoce de l'intestin et du poumon chez la Souris après irradiation par neutrons rapides et Rayons gamma.

Early repair (Elkind) after d(50) + Be neutron and gamma irradiation is assessed by determining the additional dose Dr necessary to reach a given biological effect when a single fraction Ds is split into 2 equal fractions 2Di separated by a time interval "i". LD50 at 180 days after thoracic irradiation is used as an evaluation of late pulmonary tolerance; LD50 at 5 days after abdominal irradiation is used as an evaluation of early intestinal tolerance. Dr is reduced but still important after neutron irradiation as compared to gamma irradiation. For LD50/180, after fast neutron irradiation Dr reaches 66, 90, 64, 162, 195, 150 cGy for "i" = 1, 2, 3, 5, 4, 12, and 24 hours respectively; after gamma irradiation, Field and Hornsey reported Dr = 390, 530, and 376 cGy for "i" = 2, 6, and 24 hours respectively; after neutron irradiation, they reported Dr = 190 cGy for "i" = 24 hours. For LD50/5, after fast neutron irradiation, Dr = 14, 45, 43, and 133 cGy for "i" = 1,5, 3,5, 5,5 and 24 hours respectively. Early repair is faster after gamma irradiation: Dr reaches a maximum for "i" = 3-4 hours. For neutrons, Dr reaches its maximum at 24 hours for both criteria.

Improvement of a p(65)+Be neutron beam for therapy at Cyclone, Louvain-la-Neuve.

The variable energy cyclotron of the Catholic University of Louvain is used to produce intense neutron beams for neutron therapy purposes. As a first step, neutrons were produced by bombarding a Be target with 50 MeV deuterons; at present they are produced by 65 MeV protons. This paper describes the improvements to the target system. A new (17 mm) Be target together with the old (10 mm) Be target are inserted in a movable support which allows the production of neutrons either by 65 MeV protons or by 50 MeV deuterons. Both targets can be removed for proton beam therapy. The dosimetric characteristics of the p(65)+Be and d(50)+Be neutron beams are compared: dose rate, gamma-contribution, depth dose and room activation.

Comparison of neutron therapy beams produced by 50 MeV deuterons and 65 MeV protons on beryllium.

Neutron beams produced by bombarding a 10 cm thick beryllium target with 50 MeV deuterons have been used at Louvain-la-Neuve since nearly 4 years for routine therapeutic applications. At the end of 1981 they were replaced by neutron beams produced by 65 MeV protons on beryllium, mainly in order to improve the beam penetration in tissues. However, produced of neutrons from the p leads to Be reaction implies some disadvantages, mainly a lower dose rate and a higher activation level. In order to solve the problem a new target configuration was designed, consisting of a remote handled system which permits the use of 2 different target assemblies. The irradiated target is automatically removed immediately after the irradiation which greatly protects against exposure to the staff. The dosimetric characteristics of the d(50)-Be and p(65)-Be neutrons beams are compared.