State of The Art of Instrumentation in Experimental Nanodosimetry.

Nanodosimetry is a branch of dosimetry for investigation and modeling of the interaction pattern of ionizing radiation in nanometre site-sizes (at unit density), which dates back to the 1970's (Pszona S. A track ion counter. Proceedings of Fifth Symposium on Microdosimetry EUR 5452 d-e-f, Published by the Commission of the European Communities, Luxemburg, pp. 1107-1122 (1976)). To date, the different experimental approaches have lead to developing of three fully functional nanodosimeters: the Jet Counter operated at NCBJ, the Ion Counter operated at PTB and Startrack Counter operated at INFN-LNL. Descriptions of each nanodosimeter as well as of the techniques used to investigate the track structure of ionizing particles are presented.

NANODOSIMETRY: TOWARDS A NEW CONCEPT OF RADIATION QUALITY.

The biological action of ionizing charged particles is initiated at the DNA level, and the effectiveness with which the initial physical effect changes into measurable biological damage is likely ruled by the stochastics of ionizations produced by the incident ions in subcellular nanometric volumes. Based on this hypothesis, experimental nanodosimetry aims at establishing a new concept of radiation quality that builds on measurable characteristics of the particle track structure at the nanometer scale. Three different nanodosimetric detection systems have been developed to date that allow measurements of the number of ionizations produced by the passage of a primary particle in a nanometer-size gas volume (in unit density scale). Within the Italian project MITRA (MIcrodosimetry and TRAck structure), funded by the Italian Istituto Nazionale di Fisica Nucleare (INFN) and the EMRP Joint Research Project 'BioQuaRT' (Biologically Weighted Quantities in Radiotherapy), experiments have been carried out, in which the frequency distribution of ionizations produced by proton and carbon ion beams of given energy was measured with the three nanodosimetric detectors. Descriptors of the track structure can be derived from these distributions. In particular, the first moment M1, representing the mean number of ionizations produced in the target volume, and the cumulative probability Fk of measuring a number ν ≥ k of ionizations. The correlation between measured nanodosimetric quantities and experimental radiobiological data available in the literature is here presented and discussed.

Nanodosimetry of electrons: analysis by experiment and modelling.

Nanodosimetry experiments for high-energy electrons from a (131)I radioactive source interacting with gaseous nitrogen with sizes on a scale equivalent to the mass per area of a segment of DNA and nucleosome are described. The discrete ionisation cluster-size distributions were measured in experiments carried out with the Jet Counter. The experimental results were compared with those obtained by Monte Carlo modelling. The descriptors of radiation damages have been derived from the data obtained from ionisation cluster-size distributions.

Experimental investigation of ionisation track structure of carbon ions at HIL Warsaw.

In view of the upcoming radiation therapy with carbon ions, the ionisation structure of the carbon ion track at the nanometre scale is of particular interest. Two different nanodosimeters capable of measuring track structure of ionising particles in a gas target equivalent to a nanometric site in condensed matter were involved in the presented experimental investigation, namely the NCBJ Jet Counter and the PTB Ion Counter. At the accelerator facility of the HIL in Warsaw, simulated nanometric volumes were irradiated with carbon ions of 45 and 76 MeV of kinetic energy, corresponding to a range in the tissue of ∼85 µm and ∼190 µm, respectively. The filling gas of both nanodosimeters' ionisation volume was molecular nitrogen N2, and the ionisation cluster size distributions, i.e. the statistical distribution of the number of ionizations produced by one single primary carbon ion in the filling gas, were measured for the two primary particle energies.

Future development of biologically relevant dosimetry.

Proton and ion beams are radiotherapy modalities of increasing importance and interest. Because of the different biological dose response of these radiations as compared with high-energy photon beams, the current approach of treatment prescription is based on the product of the absorbed dose to water and a biological weighting factor, but this is found to be insufficient for providing a generic method to quantify the biological outcome of radiation. It is therefore suggested to define new dosimetric quantities that allow a transparent separation of the physical processes from the biological ones. Given the complexity of the initiation and occurrence of biological processes on various time and length scales, and given that neither microdosimetry nor nanodosimetry on their own can fully describe the biological effects as a function of the distribution of energy deposition or ionization, a multiscale approach is needed to lay the foundation for the aforementioned new physical quantities relating track structure to relative biological effectiveness in proton and ion beam therapy. This article reviews the state-of-the-art microdosimetry, nanodosimetry, track structure simulations, quantification of reactive species, reference radiobiological data, cross-section data and multiscale models of biological response in the context of realizing the new quantities. It also introduces the European metrology project, Biologically Weighted Quantities in Radiotherapy, which aims to investigate the feasibility of establishing a multiscale model as the basis of the new quantities. A tentative generic expression of how the weighting of physical quantities at different length scales could be carried out is presented.

Low-level gamma and neutron monitoring based on use of proportional counter filled with 3He in polythene moderator: study of the responses to gamma and neutrons.

It has been shown that a proportional counter filled with (3)He placed centrally inside a polythene sphere opens a new possibility for measuring gamma photons and neutrons in the separate pulse-height windows. The responses to gamma and neutrons (in terms of ambient dose equivalent) of the detector assembly consisting of 203-mm polythene sphere with centrally positioned 40-mm diameter (3)He proportional counter have been studied. The response to secondary gammas from capture process in hydrogen has also been studied. The rather preliminary studies indicate that the proposed measuring system has very promising features as an ambient dose equivalent device for mixed gamma-neutron fields.

New descriptors of radiation quality based on nanodosimetry, a first approach.

After a short overview on the latest developments in nanodosimetry, measured frequency distributions of ionisation cluster size caused by 4.6 MeV alpha-particles or low-energy electrons in 'nanometric' volumes of nitrogen are compared with cluster-size distributions for liquid water cylinders that are equal in size to segments of DNA of 10 base-pairs length. Such frequency distributions are, to a greater part, governed by the same basic physical interaction data as those to be expected, if charged particles interact with DNA segments. Quantities derived from ionisation cluster-size distributions should, therefore, behave as a function of radiation quality similarly to the yields of single or double strand breaks in the DNA. To test this assumption, extensive Monte Carlo simulations were performed for electrons in the energy range between 12.5 eV and 100 keV for protons at energies between 0.7 MeV and 250 MeV and for alpha-particles in the energy range between 2 MeV and 100 MeV. The results are then compared with the yields of single- or double-strand breaks in the DNA, taken from the literature.

Formation of ion clusters by low-energy electrons in nanometric targets: experiment and Monte Carlo simulation.

The first experimental data on the distribution of ionisation cluster size produced by low energy electrons in a target cylinder of nitrogen, 3.5 nm in diameter at unit density, which is equivalent to approximately 2 nm in liquid water are presented. In the experiment, nanometric targets were simulated in the so-called Jet Counter. It consists of a pulse-operated valve which injects an expanding jet of nitrogen into an interaction chamber where a cylindrical sensitive volume is created. This sensitive volume was irradiated by electrons at 300 eV, 500 eV and 1 keV, emitted by an electron gun. The distribution of ionisation cluster size was measured using the single-ion-counting method and compared with the results of Monte Carlo simulation.

Ionization cluster size distribution for alpha particles: experiment, modelling.

The paper presents data for measured ionization cluster size distributions by alpha particles in tissue equivalent media and comparison with the simulated data for liquid water. The experiments were carried out with a beam of 4.6 MeV alpha particles performed in a setup called the JET Counter. The theoretically derived cluster size distributions for alphas particles were obtained using the K-means algorithm. The simulation was carried out by Monte Carlo track structure calculations using cross sections for liquid water. The first moments of cluster size distributions, derived from K-means algorithm as a function of diameter of cluster centroid, were compared with the corresponding moments derived from the experiments for nitrogen and propane targets. It was found that the ratio of the first moments for water to gas targets correlates well with the corresponding ratio of the mean free paths for primary ionization by alpha particles in the two media. It is shown that the cluster size distributions for alpha particles in water, obtained from K-means algorithm, are in agreement with the corresponding distributions measured experimentally in nitrogen or propane gas targets of nanometer sizes.

Experimental equivalent cluster-size distributions in nanometric volumes of liquid water.

Ionisation cluster-size distributions in nanometric volumes of liquid water were determined for alpha particles at 4.6 and 5.4 MeV by measuring cluster-size frequencies in small gaseous volumes of nitrogen or propane at low gas pressure as well as by applying a suitable scaling procedure. This scaling procedure was based on the mean free ionisation lengths of alpha particles in water and in the gases measured. For validation, the measurements of cluster sizes in gaseous volumes and the cluster-size formation in volumes of liquid water of equivalent size were simulated by Monte Carlo methods. The experimental water-equivalent cluster-size distributions in nitrogen and propane are compared with those in liquid water and show that cluster-size formation by alpha particles in nitrogen or propane can directly be related to those in liquid water.

Clusters of ionisation in nanometre targets for propane-experiments with a Jet Counter.

Further evidence on the reliability of the device called the Jet Counter (JC) for studying the formation of ionisation clusters at the nanometre level are presented. The new experimental data on the distributions of ionisation cluster size originating from a 2-10 nm size target in propane irradiated by 3.8 MeV alpha particles are described. The JC consists of a pulse-operated valve that injects an expanding jet of propane into an interaction chamber, where a sensitive volume in the form of a cylinder is created. The sensitive volume was irradiated by 3.8 MeV alpha particles. The resulting distribution of ion clusters, ranging from 2 to 10 nm in unit density gas, has been measured. A method of determining the efficiency of registration of single propane ions using an ion detector is described. A method of deconvolution of the measured to true cluster size distributions is also given. Finally, the measured cluster size distributions are compared with modelled distributions based on Monte Carlo calculations. The results for propane together with previous ones for nitrogen indicate the JC to be an efficient tool for the investigation of radiation quality at the nanometre level.

The track structure of alpha-particles from the point of view of ionization-cluster formation in "nanometric" volumes of nitrogen.

Probability distributions of the size of ion clusters created in "nanometric" volumes of nitrogen by single alpha-particles of a gold-plated 241Am source, were measured and compared with those calculated by Monte Carlo methods in the same geometry. The diameter of the sensitive volumes had a mass per area of between 0.015 microgram/cm2 and 1.3 micrograms/cm2 which, for a material at unit density, corresponds to a nanometric target volume 0.15-13 nm in diameter. These nanometre sizes were simulated experimentally in a device called the Jet Counter. This consists of a pulse-operated valve which injects into an interaction chamber an expansion jet of molecular nitrogen gas, which is crossed by a narrow beam of alpha-particles. The resulting ions are counted and analyzed from the point of view of ionization cluster formation. The measured or calculated cluster size probabilities prove that the formation of ionization clusters along a "nanometre" track is governed by Poisson's law only in the case of very small target volumes, due to the contributions by secondary electrons. The present ionization cluster probabilities produced in "nanometric" volumes 0.15-13 nm in diameter, are the first ever determined experimentally and confirmed by Monte Carlo simulation.

The formation of ionisation clusters by alpha particles in 'nanometric' volumes of nitrogen: experiment and calculation.

Probability distributions of the size of ion clusters created in 'nanometric' cylindrical volumes of nitrogen by single 4.6 MeV alpha particles were measured and compared with those calculated by Monte Carlo simulation. The diameter of the sensitive volume had a mass per area of between 0.015 and 1.3 micrograms.cm-2 which, for a material at unit density, corresponds to a diameter of between 0.15 nm and 13 nm. These nanometre sizes were simulated experimentally in a device called Jet Counter. The measured or calculated cluster size probabilities confirmed that the formation of ionisation clusters along a 'nanometre' track can be characterised by Poisson's distribution only for very small targets. The present ionisation cluster probabilities produced in 'nanometric' volumes, 2 to 10 nm in diameter, are the first ever determined experimentally and confirmed by Monte Carlo simulation.

Ionisation clusters at DNA level: experimental modelling.

The importance of initial clustered damage to DNA is a hypothesis, which has to be approached also from physical modelling of the initial products of single charged particle interaction with DNA. A new tool for such studies, presented here, is based on modelling of the ionisation patterns resulting from a single charged particle crossing a nitrogen cavity of nanometre size. The nanometre size sites equivalent in unit density to DNA and nucleosome, have been modelled in a device, called a Jet Counter, consisting of a pulse operated valve which injects nitrogen in the form of an expansion jet into an interaction chamber. The distributions of the number of ions in a cluster created by a single alpha particle of 4.6 MeV along 0.15 nm to 13 nm size in nitrogen have been measured. A new descriptor of radiation action at DNA level is proposed.