NICE (Neutron-Induced Carcinogenic Effects)
History
 NNS
 Carcinogenesis

The NICE research project aims to improve our understanding of the biophysical effects surrounding neutron dose deposition in human tissue.

PI: John Kildea

Collaborators:

  • Michael Evans (McGill)
  • Norma Ybarra (McGill)
  • Richard Richardson (CNL)
  • Jacques Dubeau (Detec Inc.)
  • Ioannis Ragoussis (McGill Genome Centre)
  • Patricia Tonin (RI-MUHC Cancer Research Program)

Current team members:

  • Luc Galarneau (research associate)
  • Logan Montgomery, M.Sc. (Ph.D. candidate)
  • Laura Patterson, M.Sc. (Ph.D. candidate)
  • Felix Mathew, M.Sc. (Ph.D. candidate)
  • James Manalad, B.Sc. (M.Sc candidate)

Former team members:

  • Chris Lund (M.Sc.)
  • Georges Al Makdessi (M.Sc.)
  • Robert Maglieri (M.Sc.)
  • Rafael Khatchadourian (M.Sc.)
Some members of the NICE research team

Part of the NICE research team with the Nested
Neutron Spectrometer. Left to right: Robert Maglieri,
Michael Evans, John Kildea, Angel Licea.

Published Research Papers by the NICE team

F. Mathew, G. Al Makdessi, L. Montgomery, M. Evans, and J. Kildea. The impact of treatment parameter variation on secondary neutron spectra in high-energy electron beam radiotherapy. Accepted for publication in the European Journal of Medical Physics (Physica Medica), 2020.

F. Mathew, C. Chilian, L. Montgomery, and J. Kildea. Development of a passive gold-foil nested neutron spectrometer to validate the active current-mode He-3 measurements in a high neutron fluence rate radiotherapy environment. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 985:164662, 2020.

L. Montgomery, A. Landry, G. Al Makdessi, F. Mathew, and J. Kildea. A novel MLEM stopping criterion for unfolding neutron fluence spectra in radiation therapy. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 957:163400, 2020.
 
C. Lund, G. Famulari, L. Montgomery, and J. Kildea. A microdosimetric analysis of the interactions of mono-energetic neutrons with human tissue. Physica Medica, 73:29–42, 2020.

L. Montgomery, M. Evans, L. Liang, R. Maglieri, and J. Kildea. The effect of the flattening filter on photoneutron production at 10 MV in the Varian truebeam linear accelerator. Medical physics (doi.org/10.1002/mp.13148), 2018.

F. Ali, J. Atanackovic, C. Boyer, A. Festarini, J. Kildea, L. Paterson, R. Rogge, M. Stuart, and R. B. Richardson. Dosimetric and microdosimetric analyses for blood exposed to reactor- derived thermal neutrons. Journal of Radiological Protection, 2018.

J. Kildea. The Canadian neutron-induced carcinogenic effects research program-a research program to investigate neutron relative biological effectiveness for carcinogenesis with a particular focus on secondary (by-product) neutrons in high-energy radiation therapy. Radiation Environment Medicine, 6(2):55–61, 2017.

R. Maglieri, A. Licea, M. Evans, J. Seuntjens, and J. Kildea. Measuring neutron spectra in radiotherapy using the Nested Neutron Spectrometer. Medical physics, 42(11):6162–6169, 2015.


Funding: This research program is currently funded by NSERC and the Canadian Space Agency.

Students Rafael Khatchadourian, Robert Maglieri and Georges Al Makdessi were supported by grants from the Canadian Nuclear Safety Commission. The research of Georges Al Makdessi and Robert Maglieri was partially supported by MPRTN/CREATE. Laura Paterson's studies are supported by Canadian Nuclear Laboratories.

Industrial Partners: We have an ongoing collaboration with Canadian Nuclear Laboratories and Detec Inc. specifically for this project.

Project Description:

The NICE research project aims to improve our understanding of the biophysical effects surrounding radiation dose deposition in human tissue using neutrons.

Ionizing radiation is a potent carcinogen that is encountered in our natural and artificial environments. We cannot avoid it. Thankfully, radiological protection laws and regulations protect individuals from the carcinogenic risk that excess ionizing radiation poses. However, while these measures guard against unjustified use of radiation, they cannot protect three distinct populations:

  • Radiotherapy and radiology patients, for whom the out-of-field radiation dose is limited only by the justification (i.e. prescription) of the medical practitioner,
  •  Astronauts travelling in deep space who will be exposed to a low-dose smorgasbord of cosmic rays, and
  • Individuals who may be exposed to unknown radiation levels in the unlikely, but not impossible, event of a nuclear accident, atomic bomb, or terrorist attack involving an improvised nuclear device.

Accordingly, any improvement to our understanding of radiation-induced carcinogenesis will help clinicians, policy-makers, and first responders make informed decisions to protect these populations.

In our research program, we are working to improve our understanding of the etiology of radiation-induced cancer by studying neutrons. We are focusing on neutrons because their effectiveness at causing cancer is known to be energy-dependent, which suggests an underlying energy-dependent mechanism by which neutrons damage DNA. We are examining the biophysics involved using a combination of neutron spectral measurements (physics), Monte Carlo modelling (physics and chemistry), and cell irradiation experiments (biology). Specifically, we are aiming to predict the relative mutation signatures that neutrons of different energies will induce in the DNA of irradiated cells. Using the neutron sources available to us (radiotherapy accelerators, reactors, and neutron generators), we will experimentally test our predictions by irradiating cells in vitro and examining the mutational signatures induced in them using a novel single-cell DNA sequencing protocol that our group is pioneering. Our combination of modelling and experiment will provide us with unique insight into the biophysical action of ionizing radiation.

The results of our research should be of interest to researchers in the radiation medicine, space travel, and nuclear emergency preparedness fields, and our program will provide a rich multi-disciplinary environment to train the next generation of Canadian radiation biology and radiation protection researchers.

Proton therapy - Skandion Clinic
Proton therapy bunker at the Skandion Clinic, Uppsala, Sweden. Our team measured
the neutron spectrum around one of the Skandion proton beams in April 2015.

Robert_Maglieri_Thesis.pdf

History of Neutron Studies at McGill

Our interest in neutrons was originally motivated by shielding design requirements for the radiotherapy facilities under construction at the MUHC Glen site. Graduate student Rafael Khatchadourian undertook an M.Sc. project in 2011 supervised by John Kildea and Michael Evans. The goal of Rafael's work was to measure neutron ambient equivalent dose in radiotherapy bunkers and to compare measurements with Monte Carlo models. Rafael's studies were funded by a grant from the Canadian Nuclear Safety Commission.

Following from Rafael's studies, Robert Maglieri joined our research group for his M.Sc. research and helped innovate the use of a new Canadian-made neutron spectrum, the Nested Neutron Spectrometer (NNS) (Detec Inc., Gatineau, Quebec) for use in radiotherapy. Robert adopted the Maximum-likelihood, expectation-maximization (MLEM) deconvolution method to unfold raw NNS data. 

NNS
Schematic cross section of the cylindrical NNS system showing the
central He-3 detector and all seven moderators.
Canadian Common CV forKildea_John_DGFull_201

The NNS
Our research, which was the subject of Robert's M.Sc. project, (click here for the M.Sc. thesis of Robert Maglieri) demonstrated that the NNS may be used to measure the energy spectra of neutrons produced by radiotherapy beams. Our report (Maglieri et al., 2015, editor's picks Medical Physics, November 2015) into the first use of this active neutron detector in the radiation field of a medical linac has opened the possibility for practical neutron spectral measurements in radiotherapy. Until now, such measurements could only be made using cumbersome, passive readout techniques requiring days or weeks of work. With the NNS we can characterize the neutron spectrum at several points within a radiotherapy bunker (photon or proton) in just one afternoon.

NNS radiotherapy spectra
Measured (solid) and simulated (dashed) neutron spectra in the bunker of a Varian 21EX linac operated at
18 MV. The shaded region shows the statistical uncertainty associated with the measurements.

The following papers and presentations describe our work with the NNS in detail:










From Neutron Spectral Measurements to Studying Neutron-induced Carcinogenesis

Our work with the NNS has provided us with the experience and the motivation to attempt to convert neutron spectral measurements into biologically-meaningful dose estimates. We have shown that we can reliably measure neutron spectra, but, due to the poor understanding of neutron-induced carcinogenesis, we are unable to use these spectra to advise physicians or patients regarding biological damage (carcinogenesis).

With this in mind we have formed a collaboration between McGill, Canadian Nuclear Laboratories (Chalk River, Ontario), the Canadian Nuclear Safety Commission, and Detec Inc. to investigate neutron carcinogenesis through a combination of measurements and Monte Carlo modelling. Our approach is similar to that of the European ANDANTE project but it underpinned by our new measurement technique using the NNS and the excellent radio-biological facilities at Chalk River.

NICE team
Some members of the McGill-CNL collaboration on a visit to
CNL's Chalk River laboratories in October, 2015

The problem summarized:

  • The relative biological effectiveness of neutrons for carcinogenesis is energy dependent. This is borne out in the ICRP's radiation weighting factors vs energy plot for neutrons. See below.
  • In order to determine neutron equivalent dose, one must measure the neutron spectrum. With the NNS, we can measure neutron spectra!
  • But, to convert measured spectra into biologically meaningful dose (eg personal equivalent dose), we need reliable radiation weighting factors. The ICRP factors are not reliable.
  • We aim to study neutron DNA damage and its relationship to neutron energy as a way to improve our understanding of neutron carcinogenesis.
    ICRP radiation weighting factors for neutrons

The ICRP radiation weighting factors for neutrons. Red areas show approximate
energy ranges for the neutron sources at CNL and at McGill. Figure adapted from ICRP Report 103.

Over the next few years we aim to:

  1. Characterize neutron sources at CNL and at McGill using the NNS and Monte Carlo modelling.
  2. Model (and measure as much as possible) neutron spectra for realistic measurement conditions at CNL.
  3. Select measurement conditions that provide the most different energies at the point of measurement (and likely most different neutron DNA damage for tissue/cells at that point).
  4. Irradiate human lymphocyte cells under the selected measurement conditions and quantify DNA damage as a function of neutron energy.

The figure below graphically describes the objectives of the NICE project. Watch this space!!


Objectives

Objectives of the NICE project to investigate the biophysics underlying neutron DNA damage.




Maintained by John Kildea
Last updated: 30 November 2020